Imidazopyridines syk inhibitors

ABSTRACT

Certain imidazopyridines and pharmaceutical compositions thereof are provided herein. Methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of Syk activity, which comprises administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are provided. Also provided are methods for determining the presence or absence of Syk kinase in a sample.

FIELD OF THE INVENTION

Provided herein are certain imidazopyridines, compositions, and methodsof their manufacture and use.

BACKGROUND

Protein kinases, the largest family of human enzymes, encompass wellover 500 proteins. Spleen Tyrosine Kinase (Syk) is a member of the Sykfamily of tyrosine kinases, and is a regulator of early B-celldevelopment as well as mature B-cell activation, signaling, andsurvival.

Syk is a non-receptor tyrosine kinase that plays critical roles inimmunoreceptor- and integrin-mediated signaling in a variety of celltypes, including B-cells, macrophages, monocytes, mast cells,eosinophils, basophils, neutrophils, dendritic cells, platelets, andosteoclasts Immunoreceptors as described here include classicalimmunoreceptors and immunoreceptor-like molecules. Classicalimmunoreceptors include B-cell and T-cell antigen receptors as well asvarious immunoglobulin receptors (Fc receptors). Immunoreceptor-likemolecules are either structurally related to immunoreceptors orparticipate in similar signal transduction pathways and are primarilyinvolved in non-adaptive immune functions, including neutrophilactivation, natural killer cell recognition, and osteoclast activity.Integrins are cell surface receptors that play key roles in the controlof leukocyte adhesion and activation in both innate and adaptiveimmunity.

Ligand binding leads to activation of both immunoreceptors andintegrins, which results in Src family kinases being activated, andphosphorylation of immunoreceptor tyrosine-based activation motifs(ITAMs) in the cytoplasmic face of receptor-associated transmembraneadaptors. Syk binds to the phosphorylated ITAM motifs of the adaptors,leading to activation of Syk and subsequent phosphorylation andactivation of downstream signaling pathways.

Syk is essential for B-cell activation through B-cell receptor (BCR)signaling. Syk becomes activated upon binding to phosphoryated BCR andthus initiates the early signaling events following BCR activation.B-cell signaling through BCR can lead to a wide range of biologicaloutputs, which in turn depend on the developmental stage of the B-cell.The magnitude and duration of BCR signals must be precisely regulated.Aberrant BCR-mediated signaling can cause disregulated B-cell activationand/or the formation of pathogenic auto-antibodies leading to multipleautoimmune and/or inflammatory diseases. Mice lacking Syk show impairedmaturation of B-cells, diminished immunoglobulin production, compromisedT-cell-independent immune responses and marked attenuation of thesustained calcium sign upon BCR stimulation.

A large body of evidence supports the role of B-cells and the humoralimmune system in the pathogenesis of autoimmune and/or inflammatorydiseases. Protein-based therapeutics (such as Rituxan) developed todeplete B-cells represent an approach to the treatment of a number ofautoimmune and inflammatory diseases. Auto-antibodies and theirresulting immune complexes are known to play pathogenic roles inautoimmune disease and/or inflammatory disease. The pathogenic responseto these antibodies is dependent on signaling through Fc Receptors,which is, in turn, dependent upon Syk. Because of Syk's role in B-cellactivation, as well as FcR dependent signaling, inhibitors of Syk can beuseful as inhibitors of B-cell mediated pathogenic activity, includingautoantibody production. Therefore, inhibition of Syk enzymatic activityin cells is proposed as a treatment for autoimmune disease through itseffects on autoantibody production.

Syk also plays a key role in FCεRI mediated mast cell degranulation andeosinophil activation. Thus, Syk is implicated in allergic disordersincluding asthma. Syk binds to the phosphorylated gamma chain of FCεRIvia its SH2 domains and is essential for downstream signaling. Sykdeficient mast cells demonstrate defective degranulation, arachidonicacid and cytokine secretion. This also has been shown for pharmacologicagents that inhibit Syk activity in mast cells. Treatment with Sykantisense oligonucleotides inhibits antigen-induced infiltration ofeosinophils and neutrophils in an animal model of asthma. Syk deficienteosinophils also show impaired activation in response to FCεRIstimulation. Therefore, small molecule inhibitors of Syk will be usefulfor treatment of allergy-induced inflammatory diseases including asthma.

Syk is also expressed in mast cells and monocytes and has been shown tobe important for the function of these cells. For example, Sykdeficiency in mice is associated with impaired IgE-mediated mast cellactivation, manifested as marked diminution of TNF-alpha and otherinflammatory cytokine release. Syk kinase inhibitors have also beenshown to inhibit mast cell degranulation in cell based assays.Additionally, Syk inhibitors have been shown to inhibit antigen-inducedpassive cutaneous anaphylaxsis, bronchoconstriction and bronchial edemain rats.

Thus, the inhibition of Syk activity can be useful for the treatment ofallergic disorders, autoimmune diseases and inflammatory diseases suchas: SLE, rheumatoid arthritis, multiple vasculitides, idiopathicthrombocytopenic purpura (ITP), fibrotic disease, myasthenia gravis,allergic rhinitis, chronic obstructive pulmonary disease (COPD), adultrespiratory distress syndrome (ARDs) and asthma. In addition, Syk hasbeen reported to play an important role in ligand-independent tonicsignaling through the B-cell receptor, known to be an important survivalsignal in B-cells. Thus, inhibition of Syk activity may be useful intreating certain types of cancer, including B-cell lymphoma andleukemia.

SUMMARY OF THE INVENTION

Provided is at least one chemical entity chosen from compounds ofFormula I:

and pharmaceutically acceptable salts thereof, wherein

-   -   R¹ is chosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl,        pyrazolyl, and thiazolyl, each of which is optionally        substituted, and each of which is further optionally fused to a        heterocyclic or heteroaryl group, each of which is optionally        substituted,    -   R² is chosen from substituted aryl and optionally substituted        heteroaryl; and    -   R³ is chosen from hydrogen, lower alkyl, halogen, carboxamido or        CO₂H, provided that if R² is        3-(4-(tert-butyl)benzamido)-2-methylphenyl, then R³ is lower        alkyl, provided that if R¹ is        5-(morpholine-4-carbonyl)-pyridin-2-yl, then R³ is lower alkyl;        and,        further provided that the compound of Formula I is not        6-(6-phenyl-imidazo[1,2-a]pyridin-8-ylamino)-nicotinic acid        ethyl ester or        (6-phenyl-imidazo[1,2-a]pyridin-8-yl)-pyridin-2-yl-amine.

Also provided is a pharmaceutical composition, comprising at least onechemical entity described herein, together with at least onepharmaceutically acceptable vehicle chosen from carriers, adjuvants, andexcipients.

Also provided is a method for treating a patient having a diseaseresponsive to inhibition of Syk activity, comprising administering tothe patient an effective amount of at least one chemical entitydescribed herein.

Also provided is a method for treating a patient having a disease chosenfrom cancer, autoimmune diseases, inflammatory diseases, acuteinflammatory reactions, and allergic disorders comprising administeringto the patient an effective amount of at least one chemical entitydescribed herein. Also provided is a method for treating a patienthaving polycystic kidney disease comprising administering to the patientan effective amount of at least one chemical entity described herein.

Also provided is a method for increasing sensitivity of cancer cells tochemotherapy, comprising administering to a patient undergoingchemotherapy with a chemotherapeutic agent an amount of at least onechemical entity described herein, sufficient to increase the sensitivityof cancer cells to the chemotherapeutic agent.

Also provided is a method for inhibiting ATP hydrolysis, the methodcomprising contacting cells expressing Syk with at least one chemicalentity described herein in an amount sufficient to detectably decreasethe level of ATP hydrolysis in vitro.

Also provided is a method for determining the presence of Syk in asample, comprising contacting the sample with at least one chemicalentity described herein under conditions that permit detection of Sykactivity, detecting a level of Syk activity in the sample, and therefromdetermining the presence or absence of Syk in the sample.

Also provided is a method for inhibiting B-cell activity comprisingcontacting cells expressing Syk with at least one chemical entitydescribed herein in an amount sufficient to detectably decrease B-cellactivity in vitro.

At present, selected compounds for use in the invention include, but arenot limited to:

-   N-(3,4-dimethoxyphenyl)-6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-amine,-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-5,6-dimethoxypyridin-2-amine,-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]pyrimidin-4-amine,-   N-[6-(1,3-benzothiazol-5-yl)imidazo[1,2-a]pyridin-8-yl]-5,6-dimethoxypyridin-2-amine,-   7-{8-[(5,6-dimethoxypyridin-2-yl)amino]imidazo[1,2-a]pyridin-6-yl}quinoxalin-2-o,1-   6-{8-[(5,6-dimethoxypyridin-2-yl)amino]imidazo[1,2-a]pyridin-6-yl}-1H-indazol-3-amine,-   N-[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyridin-8-yl]-5,6-dimethoxypyridin-2-amine,-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-1,5-dimethyl-1H-pyrazol-3-amine,-   6-{8-[(1-ethyl-1H-pyrazol-3-yl)amino]imidazo[1,2-a]pyridin-6-yl}-3,4-dihydro-2H-1,4-benzoxazin-3-one,-   6-{8-[(1-ethyl-1H-pyrazol-3-yl)amino]imidazo[1,2-a]pyridin-6-yl}quinazolin-2-amine,-   1,5-dimethyl-N-[6-(1-methyl-1H-1,3-benzodiazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-1H-pyrazol-3-amine,-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-5-(morpholin-4-yl)pyridin-2-amine,-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-2-methoxypyrimidin-4-amine,-   N-[6-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)imidazo[1,2-a]pyridin-8-yl]-1,5-dimethyl-1H-pyrazol-3-amine,-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-1-methyl-1H-pyrazol-3-amine,-   1,5-dimethyl-N-[6-(1-methyl-1H-1,3-benzodiazol-5-yl)imidazo[1,2-a]pyridin-8-yl]-1H-pyrazol-3-amine,-   2-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]pyridine-2,6-diamine,-   1-(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)-4-methylpiperidin-4-ol,-   2-[(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)(methyl)amino]ethan-1-ol,-   6-(1H-indazol-6-yl)-N-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-yl}imidazo[1,2-a]pyridin-8-amine,-   2-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-5-N-(2-methoxyethyl)-5-N-methylpyridine-2,5-diamine,-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-6-(morpholin-4-yl)pyridazin-3-amine;-   1-ethyl-N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-5-methyl-1H-pyrazol-3-amine;-   6-(8-{[6-(morpholin-4-yl)pyridazin-3-yl]amino}imidazo[1,2-a]pyridin-6-yl)-3,4-dihydro-2H-1,4-benzoxazin-3-one;-   1-(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)azetidin-3-ol;-   1-(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)-3-methylazetidin-3-ol;-   1-[(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)oxy]-2-methylpropan-2-ol;-   [(2S)-4-(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)morpholin-2-yl]methanol;-   N-[6-(1H-indazol-6-yl)-5-methylimidazo[1,2-a]pyridin-8-yl]-5-(morpholin-4-yl)pyridin-2-amine;-   [(2R)-4-(6-{[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]amino}pyridin-3-yl)morpholin-2-yl]methanol;-   N-[6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-yl]-2-(morpholin-4-yl)-1,3-thiazol-4-amine;-   N-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-yl}-6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyridin-8-amine;-   1-methyl-N-(6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyridin-8-yl)-1H-pyrazol-3-amine;-   N-(5-methyl-6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyridin-8-yl)-5-(morpholin-4-yl)pyridin-2-amine;-   1,5-dimethyl-N-(6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyridin-8-yl)-1H-pyrazol-3-amine;-   1-(2-hydroxyethyl)-5-(8-{[5-(morpholin-4-yl)pyridin-2-yl]amino}imidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one;-   2-[ethyl({6-[(6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyridin-8-yl)amino]pyridin-3-yl})amino]ethan-1-ol;-   1-(4-{6-[(6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyridin-8-yl)amino}pyridin-3-yl]piperazin-1-yl)ethan-1-one;-   2-[4-({6-[3-(2-hydroxyethyl)-1H-indol-6-yl]imidazo[1,2-a]pyridin-8-yl}amino)phenyl]-2-methylpropan-1-ol;-   1-{4-[6-({6-[3-(2-hydroxyethyl)-1H-indol-6-yl]imidazo[1,2-a]pyridin-8-yl}amino)pyridin-3-yl]piperazin-1-yl}ethan-1-one;-   2-{5-methyl-3-[(6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyridin-8-yl)amino]-1H-pyrazol-1-yl}ethan-1-ol;-   6-(8-{[5-(hydroxymethyl)-1-methyl-1H-pyrazol-3-yl]amino}imidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-indol-2-one;-   6-[8-({5-acetyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)imidazo[1,2-a]pyridin-6-yl]-2,3-dihydro-1H-indol-2-one;-   2-hydroxy-1-(4-{6-[(6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyridin-8-yl)amino]pyridin-3-yl}piperazin-1-yl)ethan-1-one;-   6-(8-{[1-(2-hydroxyethyl)-5-methyl-1H-pyrazol-3-yl]amino}imidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-indol-2-one;-   {1-methyl-3-[(6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyridin-8-yl)amino]-1H-pyrazol-5-yl}methanol;-   6-[8-({5-methanesulfonyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)imidazo[1,2-a]pyridin-6-yl]-2,3-dihydro-1H-indol-2-one;-   N-{5-methanesulfonyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyridin-8-amine;-   6-(8-{[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]amino}imidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-indol-2-one;-   5-(4-ethylpiperazin-1-yl)-N-(6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyridin-8-yl)pyridin-2-amine;-   2-(6-(8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)-1H-indol-3-yl)ethanol;-   N-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-yl)-6-(1H-pyrrolo[3,2-b]pyridin-6-yl)imidazo[1,2-a]pyridin-8-amine;-   N-(5-methyl-6-(1H-pyrrolo[3,2-b]pyridin-6-yl)imidazo[1,2-a]pyridin-8-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine;-   6-(8-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-5-methylimidazo[1,2-a]pyridin-6-yl)indolin-2-one;-   1-(2-(6-(1H-pyrrolo[3,2-b]pyridin-6-yl)imidazo[1,2-a]pyridin-8-ylamino)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanone;-   6-(8-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2-one;-   2-(6-(8-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)-1H-indol-3-yl)ethanol;-   5-(8-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-ylamino)imidazo[1,2-a]pyridin-6-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;-   2-(3-(6-(1H-pyrrolo[3,2-b]pyridin-6-yl)imidazo[1,2-a]pyridin-8-ylamino)-1-methyl-1H-pyrazol-5-yl)propan-2-ol;-   N-(6-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)imidazo[1,2-a]pyridin-8-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine;-   N-(6-(1H-indazol-6-yl)-5-methylimidazo[1,2-a]pyridin-8-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine;-   6-(8-(5-cyclopropyl-1H-pyrazol-3-ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2-one;-   6-(8-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2-one;-   N-(6-(1H-indol-6-yl)imidazo[1,2-a]pyridin-8-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine;-   N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-amine;-   6-(8-(5-(1-hydroxy-2-methylpropan-2-yl)pyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2-one;-   2-(6-(8-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)-1H-indazol-3-yl)ethanol;-   2-(6-(8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)-1H-indazol-3-yl)ethanol;-   N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-6-(1H-indazol-6-yl)-5-methylimidazo[1,2-a]pyridin-8-amine;-   N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-6-(1H-indol-6-yl)-5-methylimidazo[1,2-a]pyridin-8-amine;-   6-(8-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-5-methylimidazo[1,2-a]pyridin-6-yl)indolin-2-one;-   2-(6-(8-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-5-methylimidazo[1,2-a]pyridin-6-yl)-1H-indol-3-yl)ethanol;-   6-(8-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-5-methylimidazo[1,2-a]pyridin-6-yl)-N-methyl-1H-indole-3-carboxamide;-   5-methyl-N-(5-morpholinopyridin-2-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-8-amine;-   1-methyl-6-(5-methyl-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2-one;-   6-(1H-indazol-6-yl)-5-methyl-N-(5-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridin-8-amine;-   5-(8-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-5-methylimidazo[1,2-a]pyridin-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazol-2(3H)-one;-   N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-5-methyl-6-(2-methyl-1H-indol-6-yl)imidazo[1,2-a]pyridin-8-amine;-   5-ethyl-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-amine;-   5-ethyl-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-6-(1H-indol-6-yl)imidazo[1,2-a]pyridin-8-amine;-   6-(5-ethyl-8-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2-one;-   2-(1-methyl-6-(5-methyl-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)-1H-indol-3-yl)ethanol;-   5-chloro-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-6-(1H-indol-6-yl)imidazo[1,2-a]pyridin-8-amine;-   6-(5-chloro-8-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2-one;-   5-chloro-6-(1H-indazol-6-yl)-N-(5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridin-8-amine;-   2-(6-(5-chloro-8-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)-1H-indol-3-yl)ethanol;-   2-(6-(5-chloro-8-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)-1-methyl-1H-indol-3-yl)ethanol;-   5-chloro-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-amine;-   6-(5-chloro-8-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2-one;-   2-(6-(5-chloro-8-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)-1-methyl-1H-indol-3-yl)ethanol;-   2-(6-(5-chloro-8-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)-1H-indol-3-yl)ethanol;-   5-(5-chloro-8-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazol-2(3H)-one;-   N-(6-(1H-indol-6-yl)imidazo[1,2-a]pyridin-8-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-amine;-   N-(6-(1H-indol-6-yl)imidazo[1,2-a]pyridin-8-yl)-5-methylisoxazol-3-amine;-   5-fluoro-6-(1H-indazol-6-yl)-N-(5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridin-8-amine;-   N-(6-(1H-pyrazolo[4,3-b]pyridin-6-yl)imidazo[1,2-a]pyridin-8-yl)-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine;-   6-(1H-indazol-6-yl)-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridine-5-carboxamide;-   (6-(1H-indazol-6-yl)-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridin-5-yl)methanol;-   6-(1H-indazol-6-yl)-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridine-5-carboxylic    acid; and-   methyl    6-(1H-indazol-6-yl)-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridine-5-carboxylate,    and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions and General Parameters

As used herein, when any variable occurs more than one time in achemical formula, its definition on each occurrence is independent ofits definition at every other occurrence. In accordance with the usualmeaning of “a” and “the” in patents, reference, for example, to “a”kinase or “the” kinase is inclusive of one or more kinases.

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise. The following abbreviations and terms have the indicatedmeanings throughout:

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optionally substituted alkyl”encompasses both “alkyl” and “substituted alkyl” as defined below. Itwill be understood by those skilled in the art, with respect to anygroup containing one or more substituents, that such groups are notintended to introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible and/or inherentlyunstable.

“Alkyl” encompasses straight chain and branched chain having theindicated number of carbon atoms, usually from 1 to 20 carbon atoms, forexample 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. For exampleC₁-C₆ alkyl encompasses both straight and branched chain alkyl of from 1to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl,isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and thelike. Alkylene is another subset of alkyl, referring to the sameresidues as alkyl, but having two points of attachment. Alkylene groupswill usually have from 2 to 20 carbon atoms, for example 2 to 8 carbonatoms, such as from 2 to 6 carbon atoms. For example, C₀ alkyleneindicates a covalent bond and C₁ alkylene is a methylene group. When analkyl residue having a specific number of carbons is named, allgeometric isomers having that number of carbons are intended to beencompassed; thus, for example, “butyl” is meant to include n-butyl,sec-butyl, isobutyl and t-butyl; “propyl” includes n-propyl andisopropyl. “Lower alkyl” refers to alkyl groups having 1 to 4 carbons.

“Alkenyl” indicates an unsaturated branched or straight-chain alkylgroup having at least one carbon-carbon double bond derived by theremoval of one molecule of hydrogen from adjacent carbon atoms of theparent alkyl. The group may be in either the cis or trans configurationabout the double bond(s). Typical alkenyl groups include, but are notlimited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), prop-2-en-2-yl; butenyls such as but-1-en-1-yl,but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl; and the like. Insome embodiments, an alkenyl group has from 2 to 20 carbon atoms and inother embodiments, from 2 to 6 carbon atoms.

“Cycloalkyl” indicates a saturated hydrocarbon ring group, having thespecified number of carbon atoms, usually from 3 to 7 ring carbon atoms.Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl as well as bridged and caged saturated ringgroups such as norbornane.

By “alkoxy” is meant an alkyl group of the indicated number of carbonatoms attached through an oxygen bridge such as, for example, methoxy,ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy,2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy,3-methylpentoxy, and the like. Alkoxy groups will usually have from 1 to6 carbon atoms attached through the oxygen bridge. “Lower alkoxy” refersto alkoxy groups having 1 to 4 carbons.

“Aminocarbonyl” encompasses a group of the formula —(C═O)NR^(a)R^(b)where R^(a) and R^(b) are independently chosen from hydrogen and theoptional substituents for “substituted amino” described below.

“Acyl” refers to the groups (alkyl)-C(O)—; (cycloalkyl)-C(O)—;(aryl)-C(O)—; (heteroaryl)-C(O)—; and (heterocycloalkyl)-C(O)—, whereinthe group is attached to the parent structure through the carbonylfunctionality and wherein alkyl, cycloalkyl, aryl, heteroaryl, andheterocycloalkyl are as described herein. Acyl groups have the indicatednumber of carbon atoms, with the carbon of the keto group being includedin the numbered carbon atoms. For example a C₂ acyl group is an acetylgroup having the formula CH₃(C═O)—.

By “alkoxycarbonyl” is meant an ester group of the formula(alkoxy)(C═O)— attached through the carbonyl carbon wherein the alkoxygroup has the indicated number of carbon atoms. Thus a C₁-C₆alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atomsattached through its oxygen to a carbonyl linker.

By “amino” is meant the group —NH₂.

“Aryl” encompasses:

-   -   5- and 6-membered carbocyclic aromatic rings, for example,        benzene;    -   bicyclic ring systems wherein at least one ring is carbocyclic        and aromatic, for example, naphthalene, indane, and tetralin;        and    -   tricyclic ring systems wherein at least one ring is carbocyclic        and aromatic, for example, fluorene.

For example, aryl includes 5- and 6-membered carbocyclic aromatic ringsfused to a 5- to 7-membered heterocycloalkyl ring containing 1 or moreheteroatoms chosen from N, O, and S. For such fused, bicyclic ringsystems wherein only one of the rings is a carbocyclic aromatic ring,the point of attachment may be at the carbocyclic aromatic ring or theheterocycloalkyl ring. Bivalent radicals formed from substituted benzenederivatives and having the free valences at ring atoms are named assubstituted phenylene radicals. Bivalent radicals derived from univalentpolycyclic hydrocarbon radicals whose names end in “-yl” by removal ofone hydrogen atom from the carbon atom with the free valence are namedby adding “-idene” to the name of the corresponding univalent radical,e.g., a naphthyl group with two points of attachment is termednaphthylidene. Aryl, however, does not encompass or overlap in any waywith heteroaryl, separately defined below. Hence, if one or morecarbocyclic aromatic rings is fused with a heterocycloalkyl aromaticring, the resulting ring system is heteroaryl, not aryl, as definedherein.

The term “aryloxy” refers to the group —O-aryl.

The term “halo” includes fluoro, chloro, bromo, and iodo, and the term“halogen” includes fluorine, chlorine, bromine, and iodine.

“Heteroaryl” encompasses:

-   -   5- to 7-membered aromatic, monocyclic rings containing one or        more, for example, from 1 to 4, or in some embodiments, from 1        to 3, heteroatoms chosen from N, O, and S, with the remaining        ring atoms being carbon; and    -   bicyclic heterocycloalkyl rings containing one or more, for        example, from 1 to 4, or in some embodiments, from 1 to 3,        heteroatoms chosen from N, O, and S, with the remaining ring        atoms being carbon and wherein at least one heteroatom is        present in an aromatic ring.

For example, heteroaryl includes a 5- to 7-membered heterocycloalkyl,aromatic ring fused to a 5- to 7-membered cycloalkyl ring. For suchfused, bicyclic heteroaryl ring systems wherein only one of the ringscontains one or more heteroatoms, the point of attachment may be at theheteroaromatic ring or the cycloalkyl ring. When the total number of Sand O atoms in the heteroaryl group exceeds 1, those heteroatoms are notadjacent to one another. In some embodiments, the total number of S andO atoms in the heteroaryl group is not more than 2. In some embodiments,the total number of S and O atoms in the aromatic heterocycle is notmore than 1. Examples of heteroaryl groups include, but are not limitedto, (as numbered from the linkage position assigned priority 1),2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl,2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolinyl,isoxazolinyl, oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl,thienyl, benzothiophenyl, furanyl, benzofuranyl, benzoimidazolinyl,indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and5,6,7,8-tetrahydroisoquinoline. Bivalent radicals derived from univalentheteroaryl radicals whose names end in “-yl” by removal of one hydrogenatom from the atom with the free valence are named by adding “-idene” tothe name of the corresponding univalent radical, e.g., a pyridyl groupwith two points of attachment is a pyridylidene. Heteroaryl does notencompass or overlap with aryl as defined above.

Substituted heteroaryl also includes ring systems substituted with oneor more oxide (—O⁻) substituents, such as pyridinyl N-oxides.

The term “heteroaryloxy” refers to the group —O-heteroaryl.

By “heterocycloalkyl” is meant a single aliphatic ring, usually with 3to 7 ring atoms, containing at least 2 carbon atoms in addition to 1-3heteroatoms independently selected from oxygen, sulfur, and nitrogen, aswell as combinations comprising at least one of the foregoingheteroatoms. Suitable heterocycloalkyl groups include, for example (asnumbered from the linkage position assigned priority 1), 2-pyrrolinyl,2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidinyl, 3-piperidinyl,4-piperidinyl, and 2,5-piperazinyl. Morpholinyl groups are alsocontemplated, including 2-morpholinyl and 3-morpholinyl (numberedwherein the oxygen is assigned priority 1). Substituted heterocycloalkylalso includes ring systems substituted with one or more oxo moieties,such as piperidinyl N-oxide, morpholinyl-N-oxide,1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.

The term “heterocycloalkyloxy” refers to the group —O-heterocycloalkyl.

The term “nitro” refers to the group —NO2.

The term “phosphono” refers to the group —PO3H2.

“Thiocarbonyl” refers to the group —C(═O)SH.

The term “optionally substituted thiocarbonyl” includes the followinggroups:

—C(═O)S-(optionally substituted (C₁-C₆)alkyl), —C(═O)S-(optionallysubstituted aryl), C(═O)S-(optionally substituted heteroaryl), and—C(═O)S-(optionally substituted heterocycloalkyl).

The term “sulfanyl” includes the groups: —S-(optionally substituted(C₁-C₆)alkyl), —S-(optionally substituted aryl), —S-(optionallysubstituted heteroaryl), and —S-(optionally substitutedheterocycloalkyl). Hence, sulfanyl includes the group C1-C6alkylsulfanyl.

The term “sulfinyl” includes the groups: —S(O)—H, —S(O)-(optionallysubstituted (C1-C6)alkyl), —S(O)-optionally substituted aryl),—S(O)-optionally substituted heteroaryl), —S(O)-(optionally substitutedheterocycloalkyl); and —S(O)-(optionally substituted amino).

The term “sulfonyl” includes the groups: —S(O2)-H, —S(O2)-(optionallysubstituted (C1-C6)alkyl), —S(O2)-optionally substituted aryl),—S(O2)-optionally substituted heteroaryl), —S(O2)-(optionallysubstituted heterocycloalkyl), —S(O2)-(optionally substituted alkoxy),—S(O2)-optionally substituted aryloxy), —S(O2)-optionally substitutedheteroaryloxy), —S(O2)-(optionally substituted heterocyclyloxy); and—S(O2)-(optionally substituted amino).

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When a substituent is oxo (i.e., ═O) then 2hydrogens on the atom are replaced. Combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds or useful synthetic intermediates. A stable compound or stablestructure is meant to imply a compound that is sufficiently robust tosurvive isolation from a reaction mixture, and subsequent formulation asan agent having at least practical utility. Unless otherwise specified,substituents are named into the core structure. For example, it is to beunderstood that when (cycloalkyl)alkyl is listed as a possiblesubstituent, the point of attachment of this substituent to the corestructure is in the alkyl portion.

The terms “substituted” alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl (including without limitation pyridinyl, pyridizinyl,pyrazolyl, oxazolyl, pyrrolyl, thiazolyl, and imidazolyl group), unlessotherwise expressly defined, refer respectively to alkyl, cycloalkyl,aryl, heterocycloalkyl, and heteroaryl (including without limitationpyridinyl, pyridizinyl, pyrazolyl, oxazolyl, pyrrolyl, thiazolyl, andimidazolyl group) wherein one or more (such as up to 5, for example, upto 3) hydrogen atoms are replaced by a substituent independently chosenfrom: —R^(a), —OR^(b), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-),—SR^(b), guanidine, guanidine wherein one or more of the guanidinehydrogens are replaced with a lower-alkyl group, —NR^(b)R^(c), halo,cyano, oxo (as a substituent for heterocycloalkyl), nitro, —COR^(b),—CO₂R^(b), —CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —SOR^(a),—SO₂R^(a), —SO₂NR^(b)R^(c), and —NR^(c)SO₂R^(a),

-   -   where    -   R^(a) is chosen from optionally substituted C₁-C₆ alkyl,        optionally substituted cycloalkyl, optionally substituted aryl,        optionally substituted heterocycloalkyl, and optionally        substituted heteroaryl;    -   R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl,        optionally substituted aryl, and optionally substituted        heteroaryl; and    -   R^(c) is chosen from hydrogen and optionally substituted C₁-C₄        alkyl; or    -   R^(b) and R^(c), and the nitrogen to which they are attached,        form an optionally substituted heterocycloalkyl group; and    -   where each optionally substituted group is unsubstituted or        independently substituted with one or more, such as one, two, or        three, substituents independently selected from C₁-C₄ alkyl,        C₃-C₆ cycloalkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl-,        heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄ alkyl,        —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —C₁-C₄ alkyl-O—C₁-C₄        alkyl, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂,        —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄        alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro,        oxo (as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄        alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl),        —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄        alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄        alkyl, —C(O)C₁-C₄ phenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄        alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl),        —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄        alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

The term “substituted acyl” refers to the groups (substitutedalkyl)-C(O)—; (substituted cycloalkyl)-C(O)—; (substituted aryl)-C(O)—;(substituted heteroaryl)-C(O)—; and (substitutedheterocycloalkyl)-C(O)—, wherein the group is attached to the parentstructure through the carbonyl functionality and wherein substitutedalkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are asdescribed herein.

The term “substituted alkoxy” refers to alkoxy wherein the alkylconstituent is substituted (i.e., —O-(substituted alkyl)) wherein“substituted alkyl” is as described herein.

The term “substituted alkoxycarbonyl” refers to the group (substitutedalkyl)-O—C(O)— wherein the group is attached to the parent structurethrough the carbonyl functionality and wherein substituted alkyl is asdescribed herein.

The term “substituted aryloxy” refers to aryloxy wherein the arylconstituent is substituted (i.e., —O-(substituted aryl)) wherein“substituted aryl” is as described herein.

The term “substituted heteroaryloxy” refers to heteroaryloxy wherein thearyl constituent is substituted (i.e., —O-(substituted heteroaryl))wherein “substituted heteroaryl” is as described herein.

The term “substituted cycloalkyloxy” refers to cycloalkyloxy wherein thecycloalkyl constituent is substituted (i.e., —O-(substitutedcycloalkyl)) wherein “substituted cycloalkyl” is as described herein.

The term “substituted heterocycloalkyloxy” refers to heterocycloalkyloxywherein the alkyl constituent is substituted (i.e., —O-(substitutedheterocycloalkyl)) wherein “substituted heterocycloalkyl” is asdescribed herein.

The term “substituted amino” refers to the group —NHRd or —NRdRd whereeach Rd is independently chosen from: hydroxy, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substituted acyl,aminocarbonyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocycloalkyl, alkoxycarbonyl,sulfinyl and sulfonyl, each as described herein, and provided that onlyone Rd may be hydroxyl. The term “substituted amino” also refers toN-oxides of the groups —NHRd, and NRdRd each as described above.N-oxides can be prepared by treatment of the corresponding amino groupwith, for example, hydrogen peroxide or m-chloroperoxybenzoic acid. Theperson skilled in the art is familiar with reaction conditions forcarrying out the N-oxidation.

Compounds described herein include, but are not limited to, theiroptical isomers, racemates, and other mixtures thereof. In thosesituations, the single enantiomers or diastereomers, i.e., opticallyactive forms, can be obtained by asymmetric synthesis or by resolutionof the racemates. Resolution of the racemates can be accomplished, forexample, by conventional methods such as crystallization in the presenceof a resolving agent, or chromatography, using, for example a chiralhigh-pressure liquid chromatography (HPLC) column. In addition, suchcompounds include Z- and E-forms (or cis- and trans-forms) of compoundswith carbon-carbon double bonds. Where compounds described herein existin various tautomeric forms, chemical entities include all tautomericforms of the compound. Such compounds also include crystal formsincluding polymorphs and clathrates.

Compounds of Formula I also include crystalline and amorphous forms ofthose compounds, including, for example, polymorphs, pseudopolymorphs,solvates, hydrates, unsolvated polymorphs (including anhydrates),conformational polymorphs, and amorphous forms of the compounds, as wellas mixtures thereof. “Crystalline form,” “polymorph,” and “novel form”may be used interchangeably herein, and are meant to include allcrystalline and amorphous forms of the compound, including, for example,polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs(including anhydrates), conformational polymorphs, and amorphous forms,as well as mixtures thereof, unless a particular crystalline oramorphous form is referred to. Compounds of Formula I also includepharmaceutically acceptable forms of the recited compounds, includingchelates, non-covalent complexes, prodrugs, and mixtures thereof.

Compounds of Formula I also include different enriched isotopic forms,e.g., compounds enriched in the content of 2H, 3H, 11C, 13C and/or 14C.In some embodiments, the compounds are deuterated. Such deuterated formscan be made by the procedure described in U.S. Pat. Nos. 5,846,514 and6,334,997. As described in U.S. Pat. Nos. 5,846,514 and 6,334,997,deuteration may improve the efficacy and increase the duration of actionof drugs.

Deuterium substituted compounds can be synthesized using various methodssuch as described in: Dean, Dennis C.; Editor. Recent Advances in theSynthesis and Applications of Radiolabeled Compounds for Drug Discoveryand Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110;Kabalka, George W.; Varma, Rajender S. The Synthesis of RadiolabeledCompounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21),6601-21, and Evans, E. Anthony. Synthesis of radiolabeled compounds, J.Radioanal. Chem., 1981, 64(1-2), 9-32.

Chemical entities include, but are not limited to compounds describedherein and all pharmaceutically acceptable forms thereof. Hence, theterms “chemical entity” and “chemical entities” also encompasspharmaceutically acceptable salts.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, such as hydrochlorate, phosphate,diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts;as well as salts with an organic acid, such as malate, maleate,fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate,salicylate, stearate, and alkanoate such as acetate, HOOC—(CH₂)n-COOHwhere n is 0-4, and like salts. Similarly, pharmaceutically acceptablecations include, but are not limited to sodium, potassium, calcium,aluminum, lithium, and ammonium.

In addition, if the compounds described herein are obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare non-toxic pharmaceutically acceptable additionsalts.

As noted above, prodrugs also fall within the scope of compounds ofFormula I. In some embodiments, the “prodrugs” described herein includeany compound that becomes a compound of Formula I when administered to apatient, e.g., upon metabolic processing of the prodrug. Examples ofprodrugs include derivatives of functional groups, such as a carboxylicacid group, in the compounds of Formula I. Exemplary prodrugs of acarboxylic acid group include, but are not limited to, carboxylic acidesters such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, andaryloxyalkyl esters.

A “solvate” is formed by the interaction of a solvent and a compound.The term “compound” is intended to include solvates of compounds.Similarly, “salts” includes solvates of salts. Suitable solvates arepharmaceutically acceptable solvates, such as hydrates, includingmonohydrates and hemi-hydrates.

A “chelate” is formed by the coordination of a compound to a metal ionat two (or more) points. The term “compound” is intended to includechelates of compounds. Similarly, “salts” includes chelates of salts.

A “non-covalent complex” is formed by the interaction of a compound andanother molecule wherein a covalent bond is not formed between thecompound and the molecule. For example, complexation can occur throughvan der Waals interactions, hydrogen bonding, and electrostaticinteractions (also called ionic bonding). Such non-covalent complexesare included in the term “compound’.

The term “hydrogen bond” refers to a form of association between anelectronegative atom (also known as a hydrogen bond acceptor) and ahydrogen atom attached to a second, relatively electronegative atom(also known as a hydrogen bond donor). Suitable hydrogen bond donor andacceptors are well understood in medicinal chemistry (G. C. Pimentel andA. L. McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R.Taylor and O. Kennard, “Hydrogen Bond Geometry in Organic Crystals”,Accounts of Chemical Research, 17, pp. 320-326 (1984)).

“Hydrogen bond acceptor” refers to a group comprising an oxygen ornitrogen, especially an oxygen or nitrogen that is sp2-hybridized, anether oxygen, or the oxygen of a sulfoxide or N-oxide.

The term “hydrogen bond donor” refers to an oxygen, nitrogen, orheteroaromatic carbon that bears a hydrogen.group containing a ringnitrogen or a heteroaryl group containing a ring nitrogen.

As used herein the terms “group”, “radical” or “fragment” are synonymousand are intended to indicate functional groups or fragments of moleculesattachable to a bond or other fragments of molecules.

The term “active agent” is used to indicate a chemical entity which hasbiological activity. In some embodiments, an “active agent” is acompound having pharmaceutical utility. For example an active agent maybe an anti-cancer therapeutic.

The term “therapeutically effective amount” of a chemical entitydescribed herein means an amount effective, when administered to a humanor non-human patient, to provide a therapeutic benefit such asamelioration of symptoms, slowing of disease progression, or preventionof disease e.g., a therapeutically effective amount may be an amountsufficient to decrease the symptoms of a disease responsive toinhibition of Syk activity. In some embodiments, a therapeuticallyeffective amount is an amount sufficient to reduce cancer symptoms, thesymptoms of an allergic disorder, the symptoms of an autoimmune and/orinflammatory disease, or the symptoms of an acute inflammatory reaction.In some embodiments a therapeutically effective amount is an amountsufficient to decrease the number of detectable cancerous cells in anorganism, detectably slow, or stop the growth of a cancerous tumor. Insome embodiments, a therapeutically effective amount is an amountsufficient to shrink a cancerous tumor. In some embodiments, a patientsuffering from cancer may not present symptoms of being affected. Insome embodiments, a therapeutically effective amount of a chemicalentity is an amount sufficient to prevent a significant increase orsignificantly reduce the detectable level of cancerous cells or cancermarkers in the patient's blood, serum, or tissues. In some embodiments,a therapeutically effective amount may also be an amount sufficient,when administered to a patient, to detectably slow progression of thedisease, or prevent the patient to whom the chemical entity is givenfrom presenting symptoms of the allergic disorders and/or autoimmuneand/or inflammatory disease, and/or acute inflammatory response. In someembodiments, a therapeutically effective amount may also be an amountsufficient to produce a detectable decrease in the amount of a markerprotein or cell type in the patient's blood or serum. In someembodiments a therapeutically effective amount is an amount of achemical entity described herein sufficient to significantly decreasethe activity of B-cells. In some embodiments, a therapeuticallyeffective amount is an amount of a chemical entity described hereinsufficient to decrease the level of anti-acetylcholine receptor antibodyin a patient's blood with the disease myasthenia gravis.

The term “inhibition” indicates a significant decrease in the baselineactivity of a biological activity or process “Inhibition of Sykactivity” refers to a decrease in Syk activity as a direct or indirectresponse to the presence of at least one chemical entity describedherein, relative to the activity of Syk in the absence of the at leastone chemical entity. The decrease in activity may be due to the directinteraction of the compound with Syk, or due to the interaction of thechemical entity(ies) described herein with one or more other factorsthat in turn affect Syk activity. For example, the presence of thechemical entity(ies) may decrease Syk activity by directly binding tothe Syk, by causing (directly or indirectly) another factor to decreaseSyk activity, or by (directly or indirectly) decreasing the amount ofSyk present in the cell or organism.

Inhibition of Syk activity also refers to observable inhibition of Sykactivity in a standard biochemical assay for Syk activity, such as theATP hydrolysis assay described below. In some embodiments, the chemicalentity described herein has an IC50 value less than or equal to 1micromolar. In some embodiments, the chemical entity has an IC50 valueless than or equal to less than 100 nanomolar. In some embodiments, thechemical entity has an IC50 value less than or equal to 10 nanomolar.

“Inhibition of B-cell activity” refers to a decrease in B-cell activityas a direct or indirect response to the presence of at least onechemical entity described herein, relative to the activity of B-cells inthe absence of the at least one chemical entity. The decrease inactivity may be due to the direct interaction of the compound with Sykor with one or more other factors that in turn affect B-cell activity.

Inhibition of B-cell activity also refers to observable inhibition ofCD86 expression in a standard assay such as the assay described below.In some embodiments, the chemical entity described herein has an IC50value less than or equal to 10 micromolar. In some embodiments, thechemical entity has an IC50 value less than or equal to less than 1micromolar. In some embodiments, the chemical entity has an IC50 valueless than or equal to 500 nanomolar.

“B-cell activity” also includes activation, redistribution,reorganization, or capping of one or more various B-cell membranereceptors, or membrane-bound immunoglobulins, e.g., IgM, IgG, and IgD.Most B-cells also have membrane receptors for Fc portion of IgG in theform of either antigen-antibody complexes or aggregated IgG. B-cellsalso carry membrane receptors for the activated components ofcomplement, e.g., C3b, C3d, C4, and Clq. These various membranereceptors and membrane-bound immunoglobulins have membrane mobility andcan undergo redistribution and capping that can initiate signaltransduction.

B-cell activity also includes the synthesis or production of antibodiesor immunoglobulins. Immunoglobulins are synthesized by the B-cell seriesand have common structural features and structural units. Fiveimmunoglobulin classes, i.e., IgG, IgA, IgM, IgD, and IgE, arerecognized on the basis of structural differences of their heavy chainsincluding the amino acid sequence and length of the polypeptide chain.Antibodies to a given antigen may be detected in all or several classesof immunoglobulins or may be restricted to a single class or subclass ofimmunoglobulin. Autoantibodies or autoimmune antibodies may likewisebelong to one or several classes of immunoglobulins. For example,rheumatoid factors (antibodies to IgG) are most often recognized as anIgM imnnunoglobulin, but can also consist of IgG or IgA.

In addition, B-cell activity also is intended to include a series ofevents leading to B-cell clonal expansion (proliferation) from precursorB lymphocytes and differentiation into antibody-synthesizing plasmacells which takes place in conjunction with antigen-binding and withcytokine signals from other cells.

“Inhibition of B-cell proliferation” refers to inhibition ofproliferation of abnormal B-cells, such as cancerous B-cells, e.g.lymphoma B-cells and/or inhibition of normal, non-diseased B-cells. Theterm “inhibition of B-cell proliferation” indicates any significantdecrease in the number of B-cells, either in vitro or in vivo. Thus aninhibition of B-cell proliferation in vitro would be any significantdecrease in the number of B-cells in an in vitro sample contacted withat least one chemical entity described herein as compared to a matchedsample not contacted with the chemical entity(ies).

Inhibition of B-cell proliferation also refers to observable inhibitionof B-cell proliferation in a standard thymidine incorporation assay forB-cell proliferation, such as the assay described herein. In someembodiments, the chemical entity has an IC50 value less than or equal to10 micromolar. In some embodiments, the chemical entity has an IC50value less than or equal to less than 1 micromolar. In some embodiments,the chemical entity has an IC50 value less than or equal to 500nanomolar.

An “allergy” or “allergic disorder” refers to acquired hypersensitivityto a substance (allergen). Allergic conditions include eczema, allergicrhinitis or coryza, hay fever, bronchial asthma, urticaria (hives) andfood allergies, and other atopic conditions.

“Asthma” refers to a disorder of the respiratory system characterized byinflammation, narrowing of the airways and increased reactivity of theairways to inhaled agents. Asthma is frequently, although notexclusively associated with atopic or allergic symptoms.

By “significant” is meant any detectable change that is statisticallysignificant in a standard parametric test of statistical significancesuch as Student's T-test, where p<0.05.

A “disease responsive to inhibition of Syk activity” is a disease inwhich inhibiting Syk kinase provides a therapeutic benefit such as anamelioration of symptoms, decrease in disease progression, prevention ordelay of disease onset, or inhibition of aberrant activity of certaincell-types (monocytes, B-cells, and mast cells).

“Treatment” or “treating” means any treatment of a disease in a patient,including:

a) preventing the disease, that is, causing the clinical symptoms of thedisease not to develop;

b) inhibiting the disease;

c) slowing or arresting the development of clinical symptoms; and/or

d) relieving the disease, that is, causing the regression of clinicalsymptoms.

“Patient” refers to an animal, such as a mammal, that has been or willbe the object of treatment, observation or experiment. The methodsdescribed herein may be useful in both human therapy and veterinaryapplications. In some embodiments, the patient is a mammal; in someembodiments the patient is human; and in some embodiments the patient ischosen from cats and dogs.

Nomenclature

Names of compounds of the present invention are provided using ACD/Namesoftware for naming chemical compounds (Advanced Chemistry Development,Inc., Toronto). Other compounds or radicals may be named with commonnames, or systematic or non-systematic names. The naming and numberingof the compounds of the invention is illustrated with a representativecompound of Formula I:

which is namedN-(3,4-dimethoxyphenyl)-6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-amine

Compounds of Formula I

Accordingly, in typical embodiments the present invention providescompounds that function as Syk inhibitors. In typical embodiments theinvention relates to compounds of Formula I:

and pharmaceutically acceptable salts thereof, wherein

-   -   R¹ is chosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl,        pyrazolyl, and thiazolyl, each of which is optionally        substituted, and each of which is further optionally fused to a        heterocyclic or heteroaryl group, each of which is optionally        substituted,    -   R² is chosen from substituted aryl and optionally substituted        heteroaryl; and    -   R³ is chosen from hydrogen, lower alkyl, halogen, carboxamido or        CO₂H, provided that if R² is        3-(4-(tert-butyl)benzamido)-2-methylphenyl, then R³ is lower        alkyl, provided that if R¹ is        5-(morpholine-4-carbonyl)-pyridin-2-yl, then R³ is lower alkyl;        and,        further provided that the compound of Formula I is not        6-(6-phenyl-imidazo[1,2-a]pyridin-8-ylamino)-nicotinic acid        ethyl ester or (6-phenyl-imidazo amine.

In some embodiments, R¹ is chosen from phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazolyl, and thiazolyl, each of which is optionallysubstituted with one or more groups chosen from hydroxy;

-   -   —NR^(b)R^(c) wherein R^(b) is chosen from hydrogen and C₁-C₆        alkyl optionally substituted with one or two groups chosen from        hydroxy and —OC₁-C₄ alkyl and R^(c) is independently chosen from        hydrogen and C₁-C₄ alkyl optionally substituted with one or two        groups chosen from hydroxy and —OC₁-C₄ alkyl;    -   heterocycloalkyl optionally substituted with one or two groups        chosen from hydroxy, C₃-C₆ cycloalkyl, C₁-C₄ alkyl, —C₁-C₄        alkyl-OH, —C₁-C₄ alkyl-O—C₁-C₄ alkyl, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄        alkyl) (C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —C(O)(C₁-C₄ alkyl),        —C(O)(C₁-C₄ alkyl-OH), and —OC₁-C₄ alkyl;    -   —OC₁-C₆ alkyl optionally substituted with one or two groups        chosen from hydroxy, C₃-C₆ cycloalkyl, C₁-C₄ alkyl, —C₁-C₄        alkyl-OH, —C₁-C₄ alkyl-O—C₁-C₄ alkyl, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄        alkyl) (C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), and —OC₁-C₄ alkyl; and    -   C₁-C₆ alkyl optionally substituted with one or two groups chosen        from hydroxy, C₃-C₆ cycloalkyl, C₁-C₄ alkyl, —C₁-C₄ alkyl-OH,        —C₁-C₄ alkyl-O—C₁-C₄ alkyl, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄        alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), and —OC₁-C₄ alkyl.

In some embodiments, R¹ is chosen from pyridinyl, pyrimidinyl,pyridazinyl, pyrazolyl, and thiazolyl, each of which is optionallysubstituted with one or more groups chosen from:

-   -   hydroxy;    -   —NR^(b)R^(c) wherein R^(b) is chosen from hydrogen and C₁-C₆        alkyl optionally substituted with one or two groups chosen from        hydroxy and —OC₁-C₄ alkyl and R^(c) is independently chosen from        hydrogen and C₁-C₄ alkyl optionally substituted with one or two        groups chosen from hydroxy and —OC₁-C₄ alkyl;    -   heterocycloalkyl optionally substituted with one or two groups        chosen from hydroxy, —OC₁-C₄ alkyl, —C₁-C₄ alkyl-OH, and C₁-C₄        alkyl;    -   —OC₁-C₆ alkyl optionally substituted with one or two groups        chosen from hydroxy, —OC₁-C₄ alkyl, —NH₂, —N(C₁-C₄ alkyl)H, and        —N(C₁-C₄ alkyl)(C₁-C₄ alkyl); and    -   C₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments, R¹ is chosen from; 3,4-dimethoxyphenyl,4-(1-hydroxy-2-methylpropan-2-yl)phenyl, 5,6-dimethoxypyridin-2-yl,5-(morpholin-4-yl)pyridin-2-yl,(R)-5-(2-(hydroxymethyl)morpholino)pyridin-2-yl,(S)-5-(2-(hydroxymethyl)morpholino)pyridin-2-yl, 6-aminopyridin-2-yl,5-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-yl,5-((2-hydroxyethyl)(methyl)amino)pyridin-2-yl,5-((2-methoxyethyl)(methyl)amino)pyridin-2-yl,5-(3-hydroxyazetidin-1-yl)pyridin-2-yl,5-(3-hydroxy-3-methylazetidin-1-yl)pyridin-2-yl,5-(2-hydroxy-2-methylpropoxy)pyridin-2-yl,5-(ethyl(2-hydroxyethyl)amino)pyridin-2-yl,5-(4-acetylpiperazin-1-yl)pyridin-2-yl,5-(4-(2-hydroxyacetyl)piperazin-1-yl)pyridin-2-yl,5-(4-ethylpiperazin-1-yl)pyridin-2-yl, pyrimidin-4-yl,2-methoxypyrimidin-4-yl, 1-methyl-1H-pyrazol-3-yl,1-ethyl-1H-pyrazol-3-yl, 1-ethyl-5-methyl-1H-pyrazol-3-yl,1,5-dimethyl-1H-pyrazol-3-yl,1-(2-hydroxyethyl)-5-methyl-1H-pyrazol-3-yl,5-(hydroxymethyl)-1-methyl-1H-pyrazol-3-yl,6-(morpholin-4-yl)pyridazin-3-yl, and 2-morpholinothiazol-4-yl.

In some embodiments, R¹ is chosen from phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazolyl, and thiazolyl, each of which is optionallysubstituted and each of which is fused to a heterocyclic or heteroarylgroup and each of which is optionally substituted.

In some embodiments, R¹ is optionally substituted pyrazolyl fused to aheterocyclic or heteroaryl group, each of which is optionallysubstituted.

In some embodiments, R¹ is chosen from6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl,5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl, and5-methanesulfonyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl.

In some embodiments, R² is chosen from optionally substitutedheteroaryl, dihydroindolyl optionally substituted with oxo and C1-C6alkyl, and dihydrobenzoxazinyl optionally substituted with oxo.

In some embodiments, R² is chosen from 2,3-dimethyl-2H-indazol-6-yl,1H-indazolyl-6-yl, 1-methyl-1H-indazol-5-yl, 1-methyl-1H-indazol-6-yl,3,4-dihydro-2H-1,4-benzoxazin-3-one-6-yl,1-(2-hydroxyethyl)-1H-benzo[d]imidazol-2(3H)-one-5-yl, 3-amino-1H-indazol-6-yl, 1H-pyrrolo[3,2-b]pyridine-6-yl, 1,3-benzoxazol-6-yl,3,4-dihydro-2H-1,4-benzoxazin-6-yl, 2-hydroxyquinoxalin-7-yl,3-aminoquinolin-6-yl, 2,3-dihydro-1H-indol-6-yl,1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one, (3-hydroxyethyl)-1H-indol-6-yl,benzothiazolyl, 2-aminoquinazolin-6-yl, 3,3-dimethylindolin-2-one,2,3-dihydro-1H-indol-2-one, 4-fluoro-1H-indazol-6-yl,5-fluoro-1H-indazol-6-yl, and 3-amino-1H-indazol-6-yl.

In some embodiments, R² is chosen from 1H-indazolyl-6-yl,1-methyl-1H-indazol-5-yl, 1-methyl-1H-indazol-6-yl,3,4-dihydro-2H-1,4-benzoxazin-3-one-6-yl, 1,3-benzoxazol-6-yl,3-aminoquinolin-6-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, and2,3-dihydro-1H-indol-2-one-6-yl.

In some embodiments, R³ is chosen from hydrogen and methyl.

In some embodiments, R³ is hydrogen.

In all of the foregoing examples, the chemical entities can beadministered alone, as mixtures, or in combination with other activeagents.

General Syntheses:

The compounds of the invention may be prepared using methods disclosedherein and routine modifications thereof which will be apparent giventhe disclosure herein and methods well known in the art. Conventionaland well-known synthetic methods may be used in addition to theteachings herein. The synthesis of typical compounds described herein,e.g. compounds having structures described by one or more of Formula I,may be accomplished as described in the following examples.

Typical embodiments of compounds in accordance with the presentinvention may be synthesized using the general reaction scheme describedbelow. It will be apparent given the description herein that the generalschemes may be altered by substitution of the starting materials withother materials having similar structures to result in products that arecorrespondingly different. Descriptions of syntheses follow to providenumerous examples of how the starting materials may vary to providecorresponding products. Given a desired product for which thesubstituent groups are defined, the necessary starting materialsgenerally may be determined by inspection.

Starting materials are typically obtained from commercial sources orsynthesized using published methods. For synthesizing compounds whichare embodiments of the present invention, inspection of the structure ofthe compound to be synthesized will provide the identity of eachsubstituent group. The identity of the final product will generallyrender apparent the identity of the necessary starting materials by asimple process of inspection, given the examples herein.

As a general method, the compounds of the invention are typicallysynthesized by reacting a di-halogenated core (A) with an aminoderivative of the desired R¹ moiety (B) to provide an R¹ substitutedintermediate (C). This intermediate (C) is then reacted with anappropriately substituted boronic acid or dioxaborolane derivative (D),thereby coupling the desired R² moiety onto the R¹ coupled core. Whenthe reaction is substantially complete, the product of Formula I isisolated by conventional means.

Referring to Reaction Scheme 1, Step 1, a solution of a compound (B) ina polar solvent such as N,N-dimethylformamide is added an excess (suchas about 1.3 equivalents) to a compound (A), where L¹ and L² and leavinggroups which may be the same or different such as bromide and/orchloride. An organic base such as N,N-diisopropylethylamine is added andthe mixture is stirred at about 80° C.-120° C. for about 12-24 hours.The product, compound (C), is isolated and optionally purified.

Referring to Reaction Scheme 1, Step 2, an excess of compound (D) (suchas about 1.1 equivalents) and compound (C) are taken up in an aqueoussolution of base (such as 1 M sodium carbonate) and an inert solventsuch as 1,4-dioxane. The reaction mixture is sparged with nitrogen andstirred for about 5-20 min. The resulting mixture is treated with about0.1 equivalent of tetrakis(triphenylphosphine)palladium(0) and reactedunder microwave irradiation at about 110° C. to 135° C. for about 30 minto an hour. The resulting product, a compound of Formula I, is isolatedand optionally purified.

Compounds of formulas (B) and (D) may be commercially obtained or may besynthesized de novo. It will be appreciated that various R substitutentscan be modified or added either before or after the addition of the R¹and/or R² moieties. For example, in certain embodiments, the R² moietymay be coupled to the core before addition of the R¹ substituent. Also,in the case where the R¹ substituent contains a heteroaryl ring, thering may be synthesized and cyclized before or after addition of the R¹portion.

It will also be appreciated that the addition of any substituent mayresult in the production of a number of isomeric products any or all ofwhich may be isolated and purified using conventional techniques.

Optional Core Synthesis

When the core compound (A) is synthesized de novo, the R³ components ofthe compounds are typically established by selecting the appropriatereactants for core synthesis. Additional modification to provide adesired R³ substituent may be introduced using conventional techniquesas illustrated in the examples that follow.

Further Embodiments

Accordingly, provided is a method of treating a patient, for example, amammal, such as a human, having a disease responsive to inhibition ofSyk activity, comprising administrating to the patient having such adisease, an effective amount of at least one chemical entity describedherein.

In some embodiments, the chemical entities described herein may alsoinhibit other kinases, such that disease, disease symptoms, andconditions associated with these kinases is also treated.

Methods of treatment also include inhibiting Syk activity and/orinhibiting B-cell activity, by inhibiting ATP binding or hydrolysis bySyk or by some other mechanism, in vivo, in a patient suffering from adisease responsive to inhibition of Syk activity, by administering aneffective concentration of at least one chemical entity chosen describedherein. An example of an effective concentration would be thatconcentration sufficient to inhibit Syk activity in vitro. An effectiveconcentration may be ascertained experimentally, for example by assayingblood concentration of the chemical entity, or theoretically, bycalculating bioavailability.

In some embodiments, the condition responsive to inhibition of Sykactivity and/or B-cell activity is cancer, an allergic disorder and/oran autoimmune and/or inflammatory disease, and/or an acute inflammatoryreaction.

Also provided is a method of treating a patient having cancer, anallergic disorder and/or an autoimmune and/or inflammatory disease,and/or an acute inflammatory reaction, by administering an effectiveamount of at least one chemical entity described herein.

In some embodiments, the conditions and diseases that can be affectedusing chemical entities described herein, include, but are not limitedto: allergic disorders, including but not limited to eczema, allergicrhinitis or coryza, hay fever, bronchial asthma, urticaria (hives) andfood allergies, and other atopic conditions; autoimmune and/orinflammatory diseases, including but not limited to psoriasis, Crohn'sdisease, irritable bowel syndrome, Sjogren's disease, tissue graftrejection, and hyperacute rejection of transplanted organs, asthma,systemic lupus erythematosus (and associated glomerulonephritis),dermatomyositis, multiple sclerosis, scleroderma, vasculitis(ANCA-associated and other vasculitides), autoimmune hemolytic andthrombocytopenic states, Goodpasture's syndrome (and associatedglomerulonephritis and pulmonary hemorrhage), atherosclerosis,rheumatoid arthritis, chronic Idiopathic thrombocytopenic purpura (ITP),Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes,septic shock, myasthenia gravis, and the like; acute inflammatoryreactions, including but not limited to skin sunburn, inflammatorypelvic disease, inflammatory bowel disease, urethritis, uvitis,sinusitis, pneumonitis, encephalitis, meningitis, myocarditis,nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis,dermatitis, gingivitis, appendicitis, pancreatitis, and cholocystitis;polycystic kidney disease, and cancer, including but not limited to,B-cell lymphoma, lymphoma (including Hodgkin's and non-Hodgkinslymphoma), hairy cell leukemia, multiple myeloma, chronic and acutemyelogenous leukemia, and chronic and acute lymphocytic leukemia.

Syk is a known inhibitor of apoptosis in lymphoma B-cells. Defectiveapoptosis contributes to the pathogenesis and drug resistance of humanleukemias and lymphomas. Thus, further provided is a method of promotingor inducing apoptosis in cells expressing Syk comprising contacting thecell with at least one chemical entity described herein.

Combination Therapy

Also provided are methods of treatment in which at least one chemicalentity described herein is the only active agent given to a patient andalso includes methods of treatment in which at least one chemical entitydescribed herein is given to a patient in combination with one or moreadditional active agents.

Thus in some embodiments, a method of treating cancer, an allergicdisorder and/or an autoimmune and/or inflammatory disease, and/or anacute inflammatory reaction comprises administering to a patient in needthereof an effective amount of at least one chemical entity describedherein, together with a second active agent, which can be useful fortreating a cancer, an allergic disorder and/or an autoimmune and/orinflammatory disease, and/or an acute inflammatory reaction. For examplethe second agent may be an anti-inflammatory agent. Treatment with thesecond active agent may be prior to, concomitant with, or followingtreatment with at least one chemical entity described herein. In someembodiments, at least one chemical entity described herein is combinedwith another active agent in a single dosage form. Suitable antitumortherapeutics that may be used in combination with at least one chemicalentity described herein include, but are not limited to,chemotherapeutic agents, for example mitomycin C, carboplatin, taxol,cisplatin, paclitaxel, etoposide, doxorubicin, or a combinationcomprising at least one of the foregoing chemotherapeutic agents.Radiotherapeutic antitumor agents may also be used, alone or incombination with chemotherapeutic agents.

Chemical entities described herein can be useful as chemosensitizingagents, and, thus, can be useful in combination with otherchemotherapeutic drugs, in particular, drugs that induce apoptosis.

A method for increasing sensitivity of cancer cells to chemotherapy,comprising administering to a patient undergoing chemotherapy achemotherapeutic agent together with at least one chemical entitydescribed herein in an amount sufficient to increase the sensitivity ofcancer cells to the chemotherapeutic agent is also provided herein.

Examples of other chemotherapeutic drugs that can be used in combinationwith chemical entities described herein include topoisomerase Iinhibitors (camptothesin or topotecan), topoisomerase II inhibitors(e.g. daunomycin and etoposide), alkylating agents (e.g.cyclophosphamide, melphalan and BCNU), tubulin directed agents (e.g.taxol and vinblastine), and biological agents (e.g. antibodies such asanti CD20 antibody, IDEC 8, immunotoxins, and cytokines).

In some embodiments, the chemical entities described herein are used incombination with Rituximab or other agents that work by selectivelydepleting CD20+ B-cells.

Included herein are methods of treatment in which at least one chemicalentity described herein is administered in combination with ananti-inflammatory agent. Anti-inflammatory agents include but are notlimited to NSAIDs, non-specific and COX-2 specific cyclooxgenase enzymeinhibitors, gold compounds, corticosteroids, methotrexate, tumornecrosis factor receptor (TNF) receptors antagonists, immunosuppressantsand methotrexate.

Examples of NSAIDs include, but are not limited to ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors (i.e., a compound that inhibits COX-2 with an IC50 that is atleast 50-fold lower than the IC50 for COX-1) such as celecoxib,valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib.

In some embodiments, the anti-inflammatory agent is a salicylate.Salicylates include but are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be chosen from cortisone, dexamethasone,methylprednisolone, prednisolone, prednisolone sodium phosphate, andprednisone.

In some embodiments, the anti-inflammatory therapeutic agent is a goldcompound such as gold sodium thiomalate or auranofin.

In some embodiments, the anti-inflammatory agent is a metabolicinhibitor such as a dihydrofolate reductase inhibitor, such asmethotrexate or a dihydroorotate dehydrogenase inhibitor, such asleflunomide.

In some embodiments, combinations in which at least oneanti-inflammatory compound is an anti-05 monoclonal antibody (such aseculizumab or pexelizumab), a TNF antagonist, such as entanercept, orinfliximab, which is an anti-TNF alpha monoclonal antibody are used.

In some embodiments, combinations in which at least one active agent isan immunosuppressant compound such as methotrexate, leflunomide,cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil areused.

Pharmaceutical Compositions and Administration

Dosage levels of the order, for example, of from 0.1 mg to 140 mg perkilogram of body weight per day can be useful in the treatment of theabove-indicated conditions (0.5 mg to 7 g per patient per day). Theamount of active ingredient that may be combined with the vehicle toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. Dosage unit forms willgenerally contain from 1 mg to 500 mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. In some embodiments, for example, for thetreatment of an allergic disorder and/or autoimmune and/or inflammatorydisease, a dosage regimen of 4 times daily or less is used. In someembodiments, a dosage regimen of 1 or 2 times daily is used. It will beunderstood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, and rate ofexcretion, drug combination and the severity of the particular diseasein the patient undergoing therapy.

A labeled form of a chemical entity described herein can be used as adiagnostic for identifying and/or obtaining compounds that have thefunction of modulating an activity of a kinase as described herein. Thechemical entities described herein may additionally be used forvalidating, optimizing, and standardizing bioassays.

By “labeled” herein is meant that the compound is either directly orindirectly labeled with a label which provides a detectable signal,e.g., radioisotope, fluorescent tag, enzyme, antibodies, particles suchas magnetic particles, chemiluminescent tag, or specific bindingmolecules, etc. Specific binding molecules include pairs, such as biotinand streptavidin, digoxin and antidigoxin etc. For the specific bindingmembers, the complementary member would normally be labeled with amolecule which provides for detection, in accordance with knownprocedures, as outlined above. The label can directly or indirectlyprovide a detectable signal.

Compounds provided in accordance with the present invention are usuallyadministered in the form of pharmaceutical compositions. This inventiontherefore provides pharmaceutical compositions that contain, as theactive ingredient, one or more of the compounds described, or apharmaceutically acceptable salt or ester thereof, and one or morepharmaceutically acceptable excipients, carriers, including inert soliddiluents and fillers, diluents, including sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizers andadjuvants. The pharmaceutical compositions may be administered alone orin combination with other therapeutic agents. Such compositions areprepared in a manner well known in the pharmaceutical art (see, e.g.,Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia,Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rdEd. (G. S. Banker & C. T. Rhodes, Eds.)

The pharmaceutical compositions may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference, including rectal, buccal,intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

One mode for administration is parenteral, particularly by injection.The forms in which the novel compositions of the present invention maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles. Aqueous solutions insaline are also conventionally used for injection, but less preferred inthe context of the present invention. Ethanol, glycerol, propyleneglycol, liquid polyethylene glycol, and the like (and suitable mixturesthereof), cyclodextrin derivatives, and vegetable oils may also beemployed. The proper fluidity can be maintained, for example, by the useof a coating, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compoundaccording to the present invention in the required amount in theappropriate solvent with various other ingredients as enumerated above,as required, followed by filtered sterilization. Generally, dispersionsare prepared by incorporating the various sterilized active ingredientsinto a sterile vehicle which contains the basic dispersion medium andthe required other ingredients from those enumerated above. In the caseof sterile powders for the preparation of sterile injectable solutions,the preferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral administration is another route for administration of compounds inaccordance with the invention. Administration may be via capsule orenteric coated tablets, or the like. In making the pharmaceuticalcompositions that include at least one compound described herein, theactive ingredient is usually diluted by an excipient and/or enclosedwithin such a carrier that can be in the form of a capsule, sachet,paper or other container. When the excipient serves as a diluent, it canbe in the form of a solid, semi-solid, or liquid material (as above),which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 10% by weight of the active compound,soft and hard gelatin capsules, sterile injectable solutions, andsterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the invention can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902514; and 5,616,345. Another formulation for use in the methods ofthe present invention employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present invention incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient (e.g., a tablet, capsule, ampoule). Thecompounds are generally administered in a pharmaceutically effectiveamount. Preferably, for oral administration, each dosage unit containsfrom 1 mg to 2 g of a compound described herein, and for parenteraladministration, preferably from 0.1 to 700 mg of a compound a compounddescribed herein. It will be understood, however, that the amount of thecompound actually administered usually will be determined by aphysician, in the light of the relevant circumstances, including thecondition to be treated, the chosen route of administration, the actualcompound administered and its relative activity, the age, weight, andresponse of the individual patient, the severity of the patient'ssymptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction, or to protect from the acid conditions of the stomach. Forexample, the tablet or pill can comprise an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably, the compositions are administered by the oral ornasal respiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemasktent, or intermittent positive pressure breathing machine. Solution,suspension, or powder compositions may be administered, preferablyorally or nasally, from devices that deliver the formulation in anappropriate manner.

EXAMPLES

The invention is further illustrated by the following non-limitingexamples.

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

DME=dimethyl ether

DMEM=Dulbecco's modified Eagle's medium

DMF=N,N-dimethylformamide

DMSO=dimethylsulfoxide

Et₂O=diethylether

g=gram

h=hour

mg=milligram

min=minutes

mL=milliliter

mmol=millimoles

mM=millimolar

ng=nanogram

nm=nanometer

nM=nanomolar

PBS=phosphate buffered saline

μL=microliter

μM=micromolar

Example 1 Preparation ofN-{4H,6H,7H-pyrazolo[3,2-c][1,4]oxazin-2-yl}-6-{1H-pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2-a]pyridin-8-amine(1)

(3-Nitro-1H-pyrazol-5-yl)methanol (3)

A 3-L three-neck round-bottomed flask equipped with a mechanicalstirrer, addition funnel and nitrogen inlet was purged with nitrogen andcharged with 3-nitro-1H-pyrazole-5-carboxylic acid (2) (28.0 g, 178mmol) and THF (420 mL) and cooled to −5° C. using an ice/acetone bath.Borane-THF complex solution (1.0 M, 535 mL, 535 mmol) was added at arate that maintained the internal reaction temperature below 5° C. Afterthe addition was complete the cooling bath was removed and the reactionwas stirred at room temperature for 18 h. After this time the reactionwas cooled to −5° C. using an ice/acetone bath, water (70 mL) and 4Nhydrochloric acid (70 mL) was added and the reaction was stirred atreflux for 1 h in order to destroy the borane complex with pyrazole. Thereaction was cooled to room temperature and concentrated under reducedpressure to a volume of approximately 30 mL. Ethyl acetate (175 mL) wasadded and the mixture stirred for 15 min. The aqueous layer wasseparated and extracted with ethyl acetate (4×200 mL). The combinedorganic layers were washed with saturated aqueous sodium bicarbonate(2×50 mL), brine (50 mL) and dried over sodium sulfate, the drying agentwas removed by filtration, and the filtrate concentrated under reducedpressure to afford (3) as a light yellow solid: ¹H NMR (300 MHz,DMSO-d₆) δ □13.90 (br s, 1H), 6.87 (s, 1H), 5.58 (t, 1H, J=5.4 Hz), 4.53(d, 2H, J=5.1 Hz); MS (ESI+) m/z 144.0 (M+H).

(1-(2-Bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol (4)

A 1-L three-necked round-bottomed flask equipped with a mechanicalstirrer and thermoregulator was purged with nitrogen and charged with 3(25.0 g, 175 mmol), DMF (250 mL), and cesium carbonate (70.0 g, 215mmol) was heated at 104° C. for 5 min. The reaction mixture was thencooled to 0° C. using an ice/acetone bath and dibromoethane (329 g, 1.75mol) was added portionwise (no exotherm). The reaction was stirred at 0°C. for 1 then at room temperature for 4 h. After this time a solution ofKH₂PO₄ (40 g) in water (400 mL) was added slowly. The reaction mixturestirred at room temperature for 30 min. Ethyl acetate (450 mL) was addedand the aqueous layer was separated and extracted with ethyl acetate(2×100 mL). The combined organic layers were washed with water (200 mL),brine (200 mL), dried over sodium sulfate, and the drying agent wasremoved by filtration. The filtrate was concentrated under reducedpressure to afford crude (4) as an orange oil: ¹H NMR (300 MHz, CDCl₃) δ6.85 (s, 1H), 4.82 (d, 2H, J=5.4 Hz), 4.66 (t, 2H, J=6.3 Hz), 3.83 (t,2H, J=6.3 Hz); MS (ESI+) m/z 249.9 (M+H). This material was used in thefollowing step directly.

Preparation of 2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (5)

A solution of (1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol (4)(650 mg, 2.60 mmol) in N-methylpyrrolidinone (1.5 mL) was stirred at130° C. for 6 h. After this time, the reaction was cooled to roomtemperature, diluted with methylene chloride (50 mL) and washed withwater (2×100 mL), then brine (100 mL). The combined organic layers weredried over sodium sulfate, filtered and the filtrate concentrated underreduced pressure. The resulting residue was purified by chromatography(silica, gradient, methylene chloride to 3:97 methanol/methylenechloride) to afford 2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine(5) as a white solid: ¹H NMR (400 MHz, DMSO-d₆)□□δ 6.87 (s, 1H), 4.83(s, 2H), 4.24 (t, J=5.6 Hz, 2H), 4.13 (t, J=5.6 Hz, 2H).

Preparation of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine (6)

A 500-mL Parr hydrogenation bottle was purged with nitrogen and chargedwith 2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine(5) (250 mg, 1.48mmol), ethanol (100 mL), and 10% palladium on carbon (50% wet, 50 mg dryweight). The bottle was evacuated, charged with hydrogen gas to apressure of 30 psi and shaken for 30 min at room temperature on a Parrhydrogenation apparatus. After this time, the hydrogen was evacuated andnitrogen charged into the bottle. The catalyst was removed by filtrationthrough a pad of Celite 521 and the filter cake washed with methanol (75mL). The filtrate was concentrated under reduced pressure to afford6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine (6) as a light yellowoil: ¹H NMR (400 MHz, DMSO-d₆) δ 5.26 (s, 1H), 5.20 (bs, 2H), 4.62 (s,2H), 3.97 (t, J=4.8 Hz, 2H), 3.79 (t, J=4.8 Hz, 2H).

Preparation ofN-(6-chloroimidazo[1,2-a]pyridin-8-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine(7)

A mixture of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine (6) (150mg, 1.08 mmol), 8-bromo-6-chloroimidazo[1,2-a]pyridine hydrochloridesalt (241 mg, 0.899 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (112 mg, 0.180 mmol) andcesium carbonate (731 mg, 2.24 mmol) in toluene (6 mL) and 1,4-dioxane(3 mL) was sparged with nitrogen while stirring for 10 min.Palladium(II) acetate (22 mg, 0.098 mmol) was then added and thereaction stirred at 100° C. for 2.5 h. After this time, the reaction wascooled to room temperature, diluted with a mixture of 1:4methanol/methylene chloride (100 mL) and filtered through diatomaceousearth. The filtrate was concentrated under reduced pressure and theresulting residue purified by chromatography (silica, gradient,methylene chloride to 3:97 methanol/methylene chloride) to affordN-(6-chloroimidazo[1,2-a]pyridin-8-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine(7) as an off-white solid: ¹H NMR (400 MHz, CDCl₃)□□δ 7.69 (d, J=1.6 Hz,1H), 7.61 (d, J=1.6 Hz, 1H), 7.50-7.49 (m, 2H), 7.47 (bs, 1H), 5.72 (s,1H), 4.81 (s, 2H), 4.15-4.14 (m, 4H); ESI MS m/z 290.1 [M+H]⁺.

Preparation ofN-(6-(1H-pyrrolo[3,2-b]pyridin-6-yl)imidazo[1,2-a]pyridin-8-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine(1)

A mixture ofN-(6-chloroimidazo[1,2-a]pyridin-8-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine(7) (67 mg, 0.23 mmol),6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine(85 mg, 0.35 mmol) and 1 M aqueous sodium carbonate (0.5 mL) in1,4-dioxane (1.5 mL) was sparged with nitrogen while stirring for 5 min.

Tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.035 mmol) was thenadded and the reaction heated under microwave irradiation at 145° C. for30 min. After this time, the reaction was cooled to room temperature,diluted with a mixture of 1:4 methanol/methylene chloride (75 mL) andfiltered through diatomaceous earth. The filtrate was concentrated underreduced pressure and the resulting residue purified by chromatography(silica, gradient, methylene chloride to 1:9 methanol/methylenechloride), then trituration with acetonitrile, followed by triturationwith ethyl acetate to affordN-(6-(1H-pyrrolo[3,2-b]pyridin-6-yl)imidazo[1,2-a]pyridin-8-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine(1) as a light yellow solid: mp 192-195° C.; ¹H NMR (400 MHz,DMSO-d₆)□□δ □11.43 (bs, 1H), 8.86 (s, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.35(d, J=2.0 Hz, 1H), 8.09 (d, J=1.2 Hz, 1H), 7.95-7.93 (m, 2H), 7.70 (t,J=2.8 Hz, 1H), 7.54 (d, J=0.8 Hz, 1H), 6.60 (bs, 1H), 6.02 (s, 1H), 4.77(s, 2H), 4.07-4.04 (m, 4H); ESI MS m/z 372.0 [M+H]⁺; HPLC, 3.56min, >99% (AUC).

Example 2

Preparation of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

A solution of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (2.00g, 6.39 mmol) and 0.5 M ammonia in 1,4-dioxane (100 mL) was stirred, ina sealed vessel, at 50° C. for 20 h. After this time, the reaction wasconcentrated under reduced pressure and the resulting residue purifiedby chromatography (silica, gradient, methylene chloride to 19:1methylene chloride/methanol) to afford2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine as a yellow solid: ¹HNMR (400 MHz, DMSO-d₆)□□δ □δ 6.79 (s, 1H), 4.06 (t, J=5.2 Hz, 2H), 3.91(s, 2H), 3.15 (t, J=5.2 Hz, 2H), 2.78 (bs, 1H).

Preparation of1-(2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanone

A solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (360 mg,2.14 mmol) and triethylamine (650 mg, 6.42 mmol) in methylene chloride(16 mL) was treated dropwise with acetyl chloride (202 mg, 2.57 mmol)and the reaction was stirred at room temperature for 20 h. After thistime, the reaction was concentrated under reduced pressure and theresulting residue partitioned between ethyl acetate (20 mL) and water(20 mL). The layers were separated and the aqueous phase extracted withethyl acetate (20 mL). The combined organic layers were washed withbrine (10 mL) and dried over sodium sulfate. The drying agent wasremoved by filtration and the filtrate concentrated under reducedpressure. The resulting residue was purified by chromatography (silica,gradient, methylene chloride to 49:1 methylene chloride/methanol) toafford 1-(2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanone asa white solid: ¹H NMR (400 MHz, DMSO-d₆)□□δ □6.95-6.92 (m, 1H),4.81-4.72 (m, 2H), 4.32-4.17 (m, 2H), 4.00-3.96 (m, 2H), 2.14-2.10 (m,3H).

Preparation of1-(2-amino-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanone

A round bottom flask was charged with1-(2-nitro-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanone (200 mg,0.952 mmol), ethanol (20 mL) and 10% palladium on carbon (50% wet, 80 mgdry weight). The flask was sparged with nitrogen, charged with hydrogengas to a pressure of 1 atm (balloon) and stirred for 3 h at roomtemperature. After this time, the hydrogen gas was evacuated andnitrogen charged into the flask. The catalyst was removed by filtrationthrough a pad of diatomaceous earth and the filter cake washed withmethanol (50 mL). The filtrate was concentrated under reduced pressureto afford 1-(2-amino-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanoneas a yellow foam: ¹H NMR (400 MHz, DMSO-d₆)□δ □5.28-5.26 (m, 1H),4.58-4.51 (m, 4H), 3.86-3.73 (m, 4H), 2.09-2.05 (m, 3H).

Preparation of1-(2-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanone

A mixture of1-(2-amino-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanone (167 mg,0.927 mmol), 8-bromo-6-chloroimidazo[1,2-a]pyridine hydrochloride salt(207 mg, 0.773 mmol) and cesium carbonate (630 mg, 1.93 mmol) in toluene(4 mL) was sparged with nitrogen while stirring for 10 min.Palladium(II) acetate (17 mg, 0.076 mmol) and2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (96 mg, 0.154 mmol) werethen added and the reaction stirred at reflux for 18 h. After this time,the reaction was cooled to room temperature, diluted with a mixture of1:1 methanol/methylene chloride (20 mL), filtered through diatomaceousearth and the filter cake washed with a mixture of 1:1methanol/methylene chloride (80 mL). The filtrate was concentrated underreduced pressure and the resulting residue purified by chromatography(silica, gradient, methylene chloride to 19:1 methylenechloride/methanol) to afford1-(2-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanoneas a yellow foam: ¹H NMR (400 MHz, DMSO-d₆)□□δ □9.17-9.12 (m, 1H), 8.19(d, J=2.0 Hz, 1H), 7.87 (d, J=0.8 Hz, 1H), 7.77-7.75 (m, 1H), 7.52 (s,1H), 6.07-6.03 (m, 1H), 4.74-4.64 (m, 2H), 4.15-4.01 (m, 2H), 3.93 (t,J=5.6 Hz, 2H), 2.14-2.09 (m, 3H); ESI MS m/z 331.1 [M+H]⁺.

Preparation of6-(8-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2-one

A mixture of1-(2-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethanone(89 mg, 0.27 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (90 mg,0.35 mmol) in 1 M aqueous sodium carbonate (0.54 mL) and 1,4-dioxane (2mL) was sparged with nitrogen while stirring for 5 minTetrakis(triphenylphosphine)palladium(0) (62 mg, 0.054 mmol) was thenadded and the reaction heated under microwave irradiation at 150° C. for1 h. After this time, the mixture was filtered through diatomaceousearth and the filter cake washed with a mixture of 3:7methanol/methylene chloride (100 mL). The filtrate was washed with water(20 mL), then brine (20 mL) and dried over sodium sulfate. The dryingagent was removed by filtration and the filtrate was concentrated underreduced pressure. The resulting residue was purified by chromatography(silica, gradient, methylene chloride to 19:1 methylenechloride/methanol) to afford6-(8-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2-oneas an orange-brown solid: mp 161-165° C.; ¹H NMR (400 MHz, DMSO-d₆, 107°C.□□□δ 10.09 (bs, 1H), 8.15-8.14 (m, 2H), 7.86 (d, J=1.2 Hz, 1H), 7.78(d, J=1.6 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.17(dd, J=7.6, 1.6 Hz, 1H), 7.05 (d, J=1.2 Hz, 1H), 6.04 (s, 1H), 4.68 (s,2H), 4.06 (t, J=5.6 Hz, 2H), 3.93 (t, J=5.6 Hz, 2H), 3.47 (s, 2H), 2.10(s, 3H); ESI MS m/z 428.2 [M+H]⁺; HPLC, 4.06 min, >99% (AUC).

Example 3

Preparation of 1-(6-nitropyridin-3-yl)piperazine

A mixture of 5-bromo-2-nitropyridine (3.00 g, 14.8 mmol) and piperazine(12.7 g, 147 mmol) in acetonitrile (10 mL) was stirred at reflux for 18h. After this time, the reaction was cooled to room temperature andconcentrated under reduced pressure. The residue was diluted in ethylacetate (50 mL), washed with water (2×25 mL), then brine (25 mL) anddried over sodium sulfate. The drying agent was removed by filtrationand the filtrate concentrated under reduced pressure. The resultingresidue was purified by chromatography (silica, gradient, heptane toethyl acetate) to afford 1-(6-nitropyridin-3-yl)piperazine as a yellowsolid: ¹H NMR (400 MHz, DMSO-d₆)□□δ 8.23 (d, J=2.8 Hz, 1H), 8.13 (d,J=9.2 Hz, 1H), 7.88 (dd, J=9.2, 2.8 Hz, 1H), 3.40 (t, J=4.8 Hz, 4H),2.82 (t, J=4.8 Hz, 4H), NH (1H, not observed).

Preparation of2-hydroxy-1-(4-(6-nitropyridin-3-yl)piperazin-1-yl)ethanone

A mixture of 1-(6-nitropyridin-3-yl)piperazine (1.00 g, 4.80 mmol),2-hydroxyacetic acid (438 mg, 5.76 mmol), N,N-diisopropylethylamine(1.24 g, 9.56 mmol), and(benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate(2.18 g, 4.19 mmol) was stirred at room temperature for 18 h. After thistime, the reaction was poured into ethyl acetate (50 mL) and washed withwater (2×25 mL). The organic phase was dried over sodium sulfate,filtered and the filtrate concentrated under reduced pressure to afford2-hydroxy-1-(4-(6-nitropyridin-3-yl)piperazin-1-yl)ethanone as a yellowsolid which was used in the next step without purification: ¹H NMR (400MHz, DMSO-d₆)□□δ 8.26 (d, J=3.2 Hz, 1H), 8.18 (d, J=9.2 Hz, 1H), 7.48(dd, J=9.2, 3.2 Hz, 1H), 4.67 (s, 1H), 4.14 (s, 2H), 3.63-3.56 (m, 8H);ESI MS m/z 267.1 [M+H]⁺.

Preparation of1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)-2-hydroxyethanone

A 500-mL Parr hydrogenation bottle was purged with nitrogen and chargedwith impure 2-hydroxy-1-(4-(6-nitropyridin-3-yl)piperazin-1-yl)ethanone(1.56 g, 4.80 mmol assumed), methanol (50 mL) and 10% palladium oncarbon (50% wet, 156 mg dry weight). The bottle was evacuated, chargedwith hydrogen gas to a pressure of 40 psi and shaken for 30 min at roomtemperature on a Parr hydrogenation apparatus. After this time, thehydrogen gas was evacuated and nitrogen charged into the bottle. Thecatalyst was removed by filtration through a pad of diatomaceous earthand the filter cake washed with methanol (100 mL). The filtrate wasconcentrated under reduced pressure to afford1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)-2-hydroxyethanone as a brownsolid which was used in the next step without purification: ¹H NMR (400MHz, DMSO-d₆)□□δ 7.61 (d, J=2.8 Hz, 1H), 7.21 (dd, J=9.2, 2.8, Hz, 1H),6.42 (d, J=9.2 Hz, 1H), 5.53 (s, 2H), 4.58 (t, J=4.8 Hz, 1H), 4.11 (d,J=4.8 Hz, 2H), 3.59-3.58 (m, 2H), 3.46-3.45 (m, 2H), 2.91-2.90 (m, 4H).

Preparation of1-(4-(6-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)pyridin-3-yl)piperazin-1-yl)-2-hydroxyethanone

A mixture of 8-bromo-6-chloroimidazo[1,2-a]pyridine hydrochloride salt(997 mg, 3.72 mmol), impure1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)-2-hydroxyethanone (1.10 g,4.66 mmol assumed), cesium carbonate (3.64 g, 11.2 mmol) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (431 mg, 0.745 mmol) in1,4-dioxane (15 mL) was sparged with nitrogen while stirring for 5 min.Tris(dibenzylideneacetone)dipalladium(0) (340 mg, 0.371 mmol) was thenadded and the reaction stirred at 100° C. for 18 h. After this time, thereaction was cooled to room temperature, diluted with chloroform (100mL) and filtered through diatomaceous earth. The filtrate was washedwith water (100 mL), then brine (100 mL) and dried over sodium sulfate.The drying agent was removed by filtration and the filtrate concentratedunder reduced pressure. The resulting residue was purified bychromatography (silica, gradient, methylene chloride to 1:9methanol/methylene chloride), then chromatography (silica, gradient,methylene chloride to 1:10:20 methanol/ethyl acetate/methylene chloride)to afford1-(4-(6-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)pyridin-3-yl)piperazin-1-yl)-2-hydroxyethanoneas a solid: ¹H NMR (400 MHz, DMSO-d₆)□□δ 9.17 (s, 1H), 8.32 (d, J=1.6Hz, 1H), 8.30 (d, J=1.6 Hz, 1H), 8.02 (d, J=2.8 Hz, 1H), 7.90 (d, J=1.2Hz, 1H), 7.55 (d, J=1.2 Hz, 1H), 7.46 (dd, J=9.2, 2.8 Hz, 1H), 7.38 (d,J=9.2 Hz, 1H), 4.62 (t, J=5.6 Hz, 1H), 4.14 (d, J=5.6 Hz, 2H), 3.63-3.62(m, 2H), 3.52-3.51 (m, 2H), 3.11-3.10 (m, 4H).

Preparation of1-(4-(6-(6-(1H-pyrrolo[3,2-b]pyridin-6-yl)imidazo[1,2-a]pyridin-8-ylamino)pyridin-3-yl)piperazin-1-yl)-2-hydroxyethanone

A mixture of1-(4-(6-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)pyridin-3-yl)piperazin-1-yl)-2-hydroxyethanone(250 mg, 0.646 mmol),6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine(221 mg, 0.904 mmol) and 1 M aqueous sodium carbonate (1.9 mL) in1,4-dioxane (3 mL) was sparged with nitrogen while stirring for 5 minTetrakis(triphenylphosphine)palladium(0) (75 mg, 0.065 mmol) was thenadded and the reaction heated under microwave irradiation at 150° C. for45 min. After this time, the reaction was cooled to room temperature,diluted with a mixture of 1:9 methanol/methylene chloride (75 mL) andwashed with water (75 mL), then brine (50 mL). The organic phase wasdried over sodium sulfate, filtered and the filtrate concentrated underreduced pressure. The resulting residue was purified by chromatography(silica, gradient, methylene chloride to 1:9 methanol/methylenechloride), then trituration with acetonitrile (10 mL) to afford1-(4-(6-(6-(1H-pyrrolo[3,2-b]pyridin-6-yl)imidazo[1,2-a]pyridin-8-ylamino)pyridin-3-yl)piperazin-1-yl)-2-hydroxyethanoneas an off-white solid: mp 218-220° C.; ¹H NMR (400 MHz, DMSO-d₆)□□δ□11.42 (s, 1H), 8.98 (s, 1H), 8.63-8.61 (m, 2H), 8.43 (d, J=1.2 Hz, 1H),7.99-7.96 (m, 3H), 7.71 (t, J=2.8 Hz, 1H), 7.56 (s, 1H), 7.47 (dd,J=9.2, 2.8 Hz, 1H), 7.38 (d, J=9.2 Hz, 1H), 6.61 (s, 1H), 4.61 (t, J=5.6Hz, 1H), 4.13 (d, J=5.6 Hz, 2H), 3.63-3.61 (m, 2H), 3.51-3.49 (m, 2H),3.10-3.08 (m, 4H); ESI MS m/z 469.4 [M+H]⁺; HPLC, 3.28 min, 95.9% (AUC).

Example 4

Preparation of 1-ethyl-4-(6-nitropyridin-3-yl)piperazine

A mixture of 5-bromo-2-nitropyridine (1.02 g, 5.02 mmol) and1-ethylpiperazine (1.71 g, 15.0 mmol) in N-methyl-2-pyrrolidinone (5 mL)was stirred at 120° C. for 3 h. After this time, the reaction was cooledto room temperature, poured into water (100 mL) and extracted withmethylene chloride (2×100 mL). The combined organic layers were driedover sodium sulfate, filtered and the filtrate concentrated underreduced pressure. The resulting residue was purified by chromatography(silica, gradient, 1:49 methanol/methylene chloride to 1:9methanol/methylene chloride) to afford1-ethyl-4-(6-nitropyridin-3-yl)piperazine as a yellow solid: ¹H NMR (400MHz, DMSO-d₆)□□δ 8.25 (d, J=2.8 Hz, 1H), 8.14 (d, J=9.2 Hz, 1H), 7.48(dd, J=9.2, 2.8 Hz, 1H), 3.50-3.46 (m, 4H), 2.50-2.38 (m, 4H, mergedwith DMSO peak), 2.37 (q, J=7.2 Hz, 2H), 1.02 (t, J=7.2 Hz, 3H).

Preparation of 5-(4-ethylpiperazin-1-yl)pyridin-2-amine

A 500-mL Parr hydrogenation bottle was purged with nitrogen and chargedwith 1-ethyl-4-(6-nitropyridin-3-yl)piperazine (1.13 g, 4.78 mmol),ethanol (60 mL), ethyl acetate (120 mL) and 10% palladium on carbon (50%wet, 480 mg dry weight). The bottle was evacuated, charged with hydrogengas to a pressure of 40 psi and shaken for 1 h at room temperature on aParr hydrogenation apparatus. After this time, the hydrogen gas wasevacuated and nitrogen charged into the bottle. The catalyst was removedby filtration through a pad of diatomaceous earth and the filter cakewashed with ethanol (10 mL). The filtrate was concentrated under reducedpressure to afford 5-(4-ethylpiperazin-1-yl)pyridin-2-amine as a lightyellow solid which was used in the next step without purification: ¹HNMR (400 MHz, DMSO-d₆)□□δ ¹H NMR (400 MHz, DMSO-d₆)□□δ 7.59 (d, J=2.8Hz, 1H), 7.15 (dd, J=8.8, 2.8 Hz, 1H), 6.38 (d, J=8.8 Hz, 1H), 5.36 (bs,2H), 2.93-2.91 (m, 4H), 2.50-2.49 (m, 4H, merged with DMSO peak), 2.37(q, J=7.2 Hz, 2H), 1.04 (t, J=7.2 Hz, 3H).

Preparation of6-chloro-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridin-8-amine

A mixture of impure 5-(4-ethylpiperazin-1-yl)pyridin-2-amine (1.00 g,4.85 mmol assumed), 8-bromo-6-chloroimidazo[1,2-a]pyridine hydrochloridesalt (1.30 g, 4.85 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene(634 mg, 1.02 mmol) and cesium carbonate (4.90 g, 15.0 mmol) in toluene(50 mL) was sparged with nitrogen while stirring for 10 minPalladium(II) acetate (120 mg, 0.491 mmol) was then added and thereaction stirred at reflux for 18 h. After this time, the reaction wascooled to room temperature, diluted in a mixture of 1:1methanol/methylene chloride (100 mL) and filtered through diatomaceousearth. The filtrate was concentrated under reduced pressure and theresulting residue purified by chromatography (silica, gradient, 1:19methanol/methylene chloride to 1:6 methanol/methylene chloride) toafford6-chloro-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridin-8-amineas a yellow-green solid: ¹H NMR (400 MHz, DMSO-d₆)□□δ 9.12 (s, 1H), 8.30(d, J=2.0 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 7.99 (d, J=2.8 Hz, 1H), 7.89(d, J=0.8 Hz, 1H), 7.55 (d, J=0.8 Hz, 1H), 7.43 (dd, J=8.8, 2.8 Hz, 1H),7.35 (d, J=8.8 Hz, 1H), 3.11-3.10 (m, 4H), 2.50-2.49 (m, 4H, merged withDMSO peak), 2.38-2.37 (m, 2H), 1.04 (t, J=7.2 Hz, 3H).

Preparation ofN-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-6-(1H-pyrrolo[3,2-b]pyridin-6-yl)imidazo[1,2-a]pyridin-8-amine

A mixture of6-chloro-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridin-8-amine(357 mg, 1.00 mmol),6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine(244 mg, 1.00 mmol) and 1 M aqueous sodium carbonate (1.8 mL) in1,4-dioxane (4 mL) was sparged with nitrogen while stirring for 15 min.

Tetrakis(triphenylphosphine)palladium(0) (230 mg, 0.194 mmol) was thenadded and the reaction heated under microwave irradiation at 150° C. for40 min. After this time, the mixture was cooled to room temperature andextracted with a mixture of 1:1 methanol/methylene chloride (20 mL). Theorganic phase was dry loaded onto silica and purified by chromatography(silica, gradient, 1:49 methanol/methylene chloride to 1:9methanol/methylene chloride), then trituration with acetonitrile toaffordN-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-6-(1H-pyrrolo[3,2-b]pyridin-6-yl)imidazo[1,2-a]pyridin-8-amineas a light gray solid: mp 227-230° C.; ¹H NMR (400 MHz, DMSO-d₆)□□δ□11.41 (s, 1H), 8.92 (s, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.60 (s, 1H), 8.42(s, 1H), 7.97-7.96 (m, 3H), 7.71-7.70 (m, 1H), 7.56 (s, 1H), 7.43 (dd,J=9.0, 2.4 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 6.61 (s, 1H), 3.10-3.08 (m,4H), 2.38-2.36 (m, 2H), 1.04 (t, J=6.8 Hz, 3H), CH₂ (4H, not observed);ESI MS m/z 439.6 [M+H]⁺; HPLC, 3.06 min, >99% (AUC).

Example 5

Preparation of2-(6-(8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)-1H-indol-3-yl)ethanol

A mixture6-chloro-N-(5-morpholinopyridin-2-yl)imidazo[1,2-a]pyridin-8-amine (231mg, 0.700 mmol) and2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)ethanol(220 mg, 0.766 mmol) in 1 M aqueous sodium carbonate (0.8 mL) and1,4-dioxane (3 mL) was sparged with nitrogen while stirring for 10 min

Tetrakis(triphenylphosphine)palladium(0) (97 mg, 0.084 mmol) was thenadded and the reaction heated under microwave irradiation at 150° C. for35 min. After this time, the reaction was cooled to room temperature andpartitioned between a mixture of 5:1 methylene chloride/methanol (120mL) and water (50 mL). The layers were separated and the aqueous phaseextracted with a mixture of 4:1 methylene chloride/methanol (2×50 mL).The combined organic layers were dried over sodium sulfate, filtered andthe filtrate concentrated under reduced pressure. The resulting residuewas purified by chromatography (silica, 19:1 methylenechloride/methanol), then trituration with acetonitrile to afford2-(6-(8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)-1H-indol-3-yl)ethanolas a light brown solid: mp 159-161° C.; ¹H NMR (400 MHz, DMSO-d₆)□□δ10.93 (s, 1H), 8.91 (s, 1H), 8.62 (d, J=0.8 Hz, 1H), 8.36 (s, 1H),7.97-7.95 (m, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.58 (s, 2H), 7.44 (dd,J=8.8, 2.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.29 (dd, J=8.4, 1.2 Hz,1H), 7.21 (d, J=2.0 Hz, 1H), 4.62 (bs, 1H), 3.75 (t, J=4.8 Hz, 4H),3.69-3.67 (m, 2H), 3.07 (t, J=4.8 Hz, 4H), 2.88 (t, J=7.2 Hz, 2H); ESIMS m/z 455.3 [M+H]⁺; HPLC, 4.29 min, >99% (AUC).

Example 6

Preparation of 6,8-dibromo-5-methylimidazo[1,2-a]pyridine

A mixture of 2-bromo-1,1-diethoxyethane (1.78 g, 9.03 mmol) and 48%hydrobromic acid (2 mL) was stirred at reflux for 2 h. The reaction wasthen cooled to room temperature and treated with sodium bicarbonateuntil gas evolution ceased. The mixture was filtered and the filter cakewashed with ethanol (10 mL). 3,5-Dibromo-6-methylpyridin-2-amine (1.50g, 5.62 mmol) was then added to the filtrate and the mixture stirred atreflux for 5.5 h. The reaction was then cooled to room temperature andconcentrated under reduced pressure. The residue was diluted with 0.19 Maqueous potassium carbonate (75 mL) and stirred at room temperature for1 h. After this time, the resulting suspension was filtered and thefilter cake purified by chromatography (silica, gradient, hexanes toethyl acetate) to afford 6,8-dibromo-5-methylimidazo[1,2-a]pyridine as alight orange solid: ¹H NMR (400 MHz, DMSO-d₆)□δ 8.11 (d, J=1.2 Hz, 1H),7.84 (s, 1H), 7.72 (d, J=1.2 Hz, 1H), 2.71 (s, 3H); ESI MS m/z 289.1[M+H]⁺.

Preparation of 4-(6-nitropyridin-3-yl)morpholine

A mixture of 5-bromo-2-nitropyridine (1.00 g, 4.93 mmol), morpholine(515 mg, 5.91 mmol) and N,N-diisopropylethylamine (1.91 g, 14.8 mmol) inacetonitrile (12 mL) was stirred at reflux for 16 h. After this time,the reaction was cooled to room temperature and concentrated underreduced pressure to afford 4-(6-nitropyridin-3-yl)morpholine as a yellowsolid: ¹H NMR (400 MHz, DMSO-d₆□□□δ 8.26 (d, J=3.2 Hz, 1H), 8.17 (d,J=9.2 Hz, 1H), 7.49 (dd, J=9.2, 3.2 Hz, 1H), 3.75 (t, J=4.8 Hz, 4H),3.46 (t, J=4.8 Hz, 4H)

Preparation of 5-morpholinopyridin-2-amine

A 500-mL Parr hydrogenation bottle was purged with nitrogen and chargedwith 4-(6-nitropyridin-3-yl)morpholine (370 mg, 1.77 mmol), ethanol (80mL), ethyl acetate (40 mL) and 10% palladium on carbon (50% wet, 180 mgdry weight). The bottle was evacuated, charged with hydrogen gas to apressure of 40 psi and shaken for 30 min at room temperature on a Parrhydrogenation apparatus. After this time, the hydrogen gas was evacuatedand nitrogen charged into the bottle. The catalyst was removed byfiltration through a pad of diatomaceous earth and the filter cakewashed with methanol (70 mL). The filtrate was concentrated underreduced pressure to afford 5-morpholinopyridin-2-amine as a tan solidwhich was used in the next step without purification: ¹H NMR (400 MHz,DMSO-d₆)□□δ 7.60 (d, J=3.2 Hz, 1H), 7.16 (dd, J=8.8, 3.2 Hz, 1H), 6.40(d, J=8.8 Hz, 1H), 5.38 (bs, 2H), 3.70 (t, J=4.8 Hz, 4H), 2.89 (t, J=4.8Hz, 4H).

Preparation of6-bromo-5-methyl-N-(5-morpholinopyridin-2-yl)imidazo[1,2-a]pyridin-8-amine

A mixture of impure 5-morpholinopyridin-2-amine (259 mg, 1.45 mmolassumed), 6,8-dibromo-5-methylimidazo[1,2-a]pyridine (313 mg, 1.08mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (134 mg, 0.215mmol) and cesium carbonate (879 mg, 2.70 mmol) in toluene (5 mL) wassparged with nitrogen while stirring for 10 min Palladium(II) acetate(24 mg, 0.098 mmol) was then added and the reaction stirred at refluxfor 18 h. After this time, the reaction was cooled to room temperature,diluted with a mixture of 1:1 methanol/methylene chloride (100 mL) andfiltered through diatomaceous earth. The filtrate was concentrated underreduced pressure and the resulting residue purified by chromatography(silica, gradient, methylene chloride to 1:9 methanol/methylenechloride) to afford6-bromo-5-methyl-N-(5-morpholinopyridin-2-yl)imidazo[1,2-a]pyridin-8-amineas an off-white solid: ¹H NMR (400 MHz, DMSO-d₆)□□δ 8.99 (s, 1H), 8.50(s, 1H), 7.99 (d, J=3.2 Hz, 1H), 7.91 (d, J=0.8 Hz, 1H), 7.60 (d, J=0.8Hz, 1H), 7.42 (dd, J=8.8, 3.2 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 3.75 (t,J=4.8 Hz, 4H), 3.07 (t, J=4.8 Hz, 4H), 2.65 (s, 3H).

Preparation of6-(1H-indazol-6-yl)-5-methyl-N-(5-morpholinopyridin-2-yl)imidazo[1,2-a]pyridin-8-amine

A mixture of6-bromo-5-methyl-N-(5-morpholinopyridin-2-yl)imidazo[1,2-a]pyridin-8-amine(250 mg, 0.644 mmol),6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (188 mg,0.770 mmol) and 1 M aqueous sodium carbonate (0.9 mL) in 1,4-dioxane (4mL) was sparged with nitrogen while stirring for 5 min.

Tetrakis(triphenylphosphine)palladium(0) (111 mg, 0.0960 mmol) was thenadded and the reaction heated under microwave irradiation at 135° C. for20 min. After this time, the reaction was cooled to room temperature,diluted with a mixture of 1:4 methanol/chloroform (75 mL) and filteredthrough diatomaceous earth. The filtrate was concentrated under reducedpressure and the resulting residue purified by chromatography (silica,gradient, methylene chloride to 1:9 methanol/methylene chloride), thentrituration with acetonitrile to afford6-(1H-indazol-6-yl)-5-methyl-N-(5-morpholinopyridin-2-yl)imidazo[1,2-a]pyridin-8-amineas a light yellow solid: mp 160-164° C.; ¹H NMR (400 MHz, DMSO-d₆)□□δ□13.13 (s, 1H), 8.83 (s, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.90 (d, J=0.8Hz, 1H), 7.87-7.84 (m, 2H), 7.65 (d, J=0.8 Hz, 1H), 7.53 (s, 1H), 7.39(dd, J=9.2, 3.2 Hz, 1H), 7.32 (d, J=9.2 Hz, 1H), 7.17 (dd, J=9.2, 1.2Hz, 1H), 3.71 (t, J=4.8 Hz, 4H), 3.00 (t, J=4.8 Hz, 4H), 2.47 (s, 3H);ESI MS m/z 426.2 [M+H]⁺; HPLC, 4.12 min, >99% (AUC).

Example 7

Preparation of 2-(5-methyl-3-nitro-1H-pyrazol-1-yl)ethanol

A solution of 5-methyl-3-nitro-1H-pyrazole (500 mg, 3.93 mmol) andpotassium carbonate (1.08 g, 7.81 mmol) in acetonitrile (20 mL) wastreated dropwise with 2-iodoethanol (2.00 g, 11.6 mmol) and the reactionstirred at reflux for 18 h. After this time, the reaction was cooled toroom temperature, diluted with ethyl acetate (100 mL) and filteredthrough diatomaceous earth. The filtrate was concentrated under reducedpressure and the resulting residue purified by chromatography (silica,gradient, heptane to 1:1 ethyl acetate/heptane) to afford2-(5-methyl-3-nitro-1H-pyrazol-1-yl)ethanol as a white solid: ¹H NMR(400 MHz, DMSO-d₆)□□δ 6.82 (s, 1H), 4.97 (t, J=5.2 Hz, 1H), 4.19 (t,J=5.2 Hz, 2H), 3.75 (q, J=5.2 Hz, 2H), 2.35 (s, 3H).

Preparation of 2-(3-amino-5-methyl-1H-pyrazol-1-yl)ethanol

A 500-mL Parr hydrogenation bottle was purged with nitrogen and chargedwith 2-(5-methyl-3-nitro-1H-pyrazol-1-yl)ethanol (426 mg, 2.49 mmol),ethanol (100 mL) and 10% palladium on carbon (50% wet, 85 mg dryweight). The bottle was evacuated, charged with hydrogen gas to apressure of 30 psi and shaken for 20 min at room temperature on a Parrhydrogenation apparatus. After this time, the hydrogen was evacuated andnitrogen charged into the bottle. The catalyst was removed by filtrationthrough diatomaceous earth and the filter cake washed with methanol (75mL). The filtrate was concentrated under reduced pressure to afford2-(3-amino-5-methyl-1H-pyrazol-1-yl)ethanol as an off-white solid: ¹HNMR (400 MHz, DMSO-d₆) δ 5.18 (s, 1H), 4.74 (t, J=5.2 Hz, 1H), 4.36 (bs,2H), 3.76 (t, J=5.6 Hz, 2H), 3.61-3.58 (m, 2H), 2.10 (s, 3H).

Preparation of2-(3-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)-5-methyl-1H-pyrazol-1-yl)ethanol

A mixture of 2-(3-amino-5-methyl-1H-pyrazol-1-yl)ethanol (345 mg, 2.44mmol), 8-bromo-6-chloroimidazo[1,2-a]pyridine hydrochloride salt (514mg, 1.92 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (274 mg,0.440 mmol) and cesium carbonate (1.43 g, 4.39 mmol) in toluene (3 mL)and 1,4-dioxane (3 mL) was sparged with nitrogen while stirring for 10min. Palladium(II) acetate (54 mg, 0.22 mmol) was then added and thereaction stirred at 100° C. for 2 h. After this time, the reaction wascooled to room temperature, diluted with a mixture of 1:4methanol/methylene chloride (150 mL) and filtered through diatomaceousearth. The filtrate was concentrated under reduced pressure and theresulting residue purified by chromatography (silica, gradient,methylene chloride to 1:19 methanol/methylene chloride) to afford2-(3-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)-5-methyl-1H-pyrazol-1-yl)ethanolas a green-brown foam: ¹H NMR (400 MHz, CDCl₃)□□δ 7.68 (d, J=1.6 Hz,1H), 7.51-7.47 (m, 3H), 7.42 (d, J=1.6 Hz, 1H), 5.79 (s, 1H), 4.12-4.09(m, 2H), 4.06-4.04 (m, 2H), 2.29 (s, 3H), OH (1H, not observed); ESI MSm/z 292.1 [M+H]⁺.

Preparation of2-(3-(6-(1H-pyrrolo[3,2-b]pyridin-6-yl)imidazo[1,2-a]pyridin-8-ylamino)-5-methyl-1H-pyrazol-1-yl)ethanol

A mixture of2-(3-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)-5-methyl-1H-pyrazol-1-yl)ethanol(210 mg, 0.720 mmol), tert-butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(297 mg, 0.863 mmol) and 1 M aqueous sodium carbonate (0.6 mL) in1,4-dioxane (2 mL) was sparged with nitrogen while stirring for 5 min.

Tetrakis(triphenylphosphine)palladium(0) (125 mg, 0.108 mmol) was thenadded and the reaction heated under microwave irradiation at 145° C. for30 min. After this time, the reaction was cooled to room temperature,dissolved in a mixture of 1:4 methanol/methylene chloride (75 mL) andfiltered through diatomaceous earth. The filtrate was concentrated underreduced pressure and the resulting residue purified by chromatography(silica, gradient, methylene chloride to 1:9 methanol/methylenechloride), then semi-preparative HPLC (C18, 1:19 acetonitrile with 0.05%TFA/water with 0.05% TFA to 19:1 acetonitrile with 0.05% TFA/water with0.05% TFA over 25 min) The combined column fractions were washed withsaturated aqueous sodium bicarbonate (200 mL) and dried over sodiumsulfate. The drying agent was removed by filtration and the filtrateconcentrated under reduced pressure. The resulting residue was furtherpurified by chromatography (silica, gradient, methylene chloride to 1:9methanol/methylene chloride) to afford2-(3-(6-(1H-pyrrolo[3,2-b]pyridin-6-yl)imidazo[1,2-a]pyridin-8-ylamino)-5-methyl-1H-pyrazol-1-yl)ethanolas a light brown solid: mp 127-130° C.; ¹H NMR (400 MHz, DMSO-d₆)□□δ□11.44 (bs, 1H), 8.63-8.62 (m, 2H), 8.34 (d, J=1.6 Hz, 1H), 8.08 (d,J=1.2 Hz, 1H), 7.95-7.94 (m, 1H), 7.92 (d, J=0.8 Hz, 1H), 7.70 (t, J=2.8Hz, 1H), 7.52 (d, J=1.2 Hz, 1H), 6.60-6.59 (m, 1H), 5.95 (s, 1H), 4.83(t, J=5.6 Hz, 1H), 4.01-3.98 (m, 2H), 3.77-3.74 (m, 2H), 2.25 (s, 3H);ESI MS m/z 374.2[M+H]⁺; HPLC, 3.36 min, >99% (AUC).

Example 8

Preparation of methyl3-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)-1-methyl-1H-pyrazole-5-carboxylate

A mixture of methyl 3-amino-1-methyl-1H-pyrazole-5-carboxylate (155 mg,0.999 mmol), 8-bromo-6-chloroimidazo[1,2-a]pyridine hydrochloride salt(268 mg, 1.00 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (135mg, 0.216 mmol) and cesium carbonate (997 mg, 3.05 mmol) in toluene (5mL) and 1,4-dioxane (5 mL) was sparged with nitrogen while stirring for10 min. Palladium(II) acetate (25 mg, 0.11 mmol) was then added and thereaction stirred at reflux for 18 h. After this time, the reaction wascooled to room temperature, diluted with a mixture of 1:1 ethylacetate/water (100 mL) and filtered through diatomaceous earth. Thefiltrate was concentrated under reduced pressure and the resultingresidue purified by chromatography (silica, gradient, heptane to 3:7heptane/ethyl acetate) to afford methyl3-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)-1-methyl-1H-pyrazole-5-carboxylateas a brown solid: ¹H NMR (400 MHz, DMSO-d₆)□□δ □9.37 (s, 1H), 8.24 (d,J=1.6 Hz, 1H), 7.89 (d, J=1.2 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.55 (d,J=1.2 Hz, 1H), 6.72 (s, 1H), 4.06 (s, 3H), 3.84 (s, 3H); ESI MS m/z306.2 [M+H]⁺.

Preparation of2-(3-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)-1-methyl-1H-pyrazol-5-yl)propan-2-ol

A solution of methyl3-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)-1-methyl-1H-pyrazole-5-carboxylate(765 mg, 2.50 mmol) in tetrahydrofuran (15 mL) was cooled to −78° C. inan dry ice/acetone bath, under a nitrogen atmosphere, and treated with3.0 M methyl magnesium bromide (5.0 mL). When the addition was complete,the cooling bath was removed and the reaction stirred at roomtemperature for 2 h. After this time, the reaction was cooled to 0° C.,treated with water (2.0 mL) and extracted with ethyl acetate (250 mL).The organic phase was dried over sodium sulfate, filtered and thefiltrate concentrated under reduced pressure to afford2-(3-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)-1-methyl-1H-pyrazol-5-yl)propan-2-olas a solid: ¹H NMR (400 MHz, DMSO-d₆)□□δ 8.91 (s, 1H), 8.17 (d, J=2.0Hz, 1H), 7.86 (d, J=0.8 Hz, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.52 (s, 1H),5.99 (s, 1H), 5.29 (s, 1H), 3.90 (s, 3H), 1.49 (s, 6H); ESI MS m/z 306.0[M+H]⁺.

Preparation of6-(8-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2-one

A mixture of2-(3-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)-1-methyl-1H-pyrazol-5-yl)propan-2-ol(250 mg, 0.818 mmol),6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (275 mg,1.06 mmol) and 1 M aqueous sodium carbonate (2.5 mL) in 1,4-dioxane (3mL) was sparged with nitrogen while stirring for 5 minTetrakis(triphenylphosphine)palladium(0) (94 mg, 0.081 mmol) was thenadded and the reaction heated under microwave irradiation at 150° C. for60 min. After this time, the reaction was cooled to room temperature,diluted with a mixture of 1:9 methanol/methylene chloride (150 mL) andfiltered through diatomaceous earth. The filtrate was concentrated underreduced pressure and the resulting residue purified by chromatography(silica, gradient, methylene chloride to 1:4 methanol/methylenechloride), then trituration with acetonitrile, followed by triturationwith methanol to afford6-(8-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2-oneas a light yellow solid: mp 180-182° C.; ¹H NMR (400 MHz, DMSO-d₆)□□δ□10.54 (s, 1H), 8.61 (s, 1H), 8.25 (d, J=1.6 Hz, 1H), 8.04 (d, J=1.2 Hz,1H), 7.91 (d, J=1.2 Hz, 1H), 7.51 (d, J=0.8 Hz, 1H), 7.31 (d, J=7.6 Hz,1H), 7.21 (dd, J=7.6, 1.6 Hz, 1H), 7.06 (d, J=0.8 Hz, 1H), 5.99 (s, 1H),5.27 (s, 1H), 3.92 (s, 3H), 3.53 (s, 2H), 1.50 (s, 6H); ESI MS m/z 403.1[M+H]⁺; HPLC, 4.30 min, >99% (AUC).

Example 9

Preparation of 1-tert-butyl 3-ethyl 2-(6-nitropyridin-3-yl)malonate

A solution of tert-butyl ethyl malonate (1.11 g, 5.90 mmol) inN,N-dimethylformamide (10 mL) was treated with 60% sodium hydridedispersed in mineral oil (565 mg, 14.1 mmol), under a nitrogenatmosphere, and stirred at room temperature for 30 min. A solution of5-bromo-2-nitropyridine (1.00 g, 4.93 mmol) in N,N-dimethylformamide (10mL) was then added dropwise, over 10 min, and the reaction stirred atroom temperature for a further 32 h. After this time, the reaction waspartitioned between water (100 mL) and ethyl acetate (100 mL). Thelayers were separated and the aqueous phase was extracted with ethylacetate (100 mL). The combined organic layers were washed with water(200 mL), then brine (200 mL) and dried over sodium sulfate. The dryingagent was removed by filtration and the filtrate concentrated underreduced pressure. The resulting residue was purified by chromatography(silica, gradient, heptane to 1:1 methylene chloride/heptane) to afford1-tert-butyl 3-ethyl 2-(6-nitropyridin-3-yl)malonate as a yellow oil: ¹HNMR (400 MHz, DMSO-d₆)□□δ 8.66 (d, J=2.0 Hz, 1H), 8.37 (d, J=8.4 Hz,1H), 7.26 (dd, J=8.4, 2.0 Hz, 1H), 5.27 (s, 1H), 4.20 (q, J=7.2 Hz, 2H),1.42 (s, 9H), 1.22 (t, J=7.2 Hz, 3H).

Preparation of ethyl 2-(6-nitropyridin-3-yl)acetate

A solution of 1-tert-butyl 3-ethyl 2-(6-nitropyridin-3-yl)malonate (2.40g, 7.73 mmol) in trifluoroacetic acid (20 mL) and methylene chloride (20mL) was stirred at reflux for 2 h. After this time, the reaction wascooled to room temperature and concentrated under reduced pressure. Theresulting residue was diluted with methylene chloride (100 mL), washedwith saturated aqueous sodium bicarbonate (100 mL) and dried over sodiumsulfate. The drying agent was removed by filtration and the filtrateconcentrated under reduced pressure to afford ethyl2-(6-nitropyridin-3-yl)acetate as an orange oil: ¹H NMR (400 MHz,DMSO-d₆)□□δ 8.59 (d, J=2.0 Hz, 1H), 8.31 (d, J=8.4 Hz, 1H), 8.17 (dd,J=8.4, 2.0 Hz, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.98 (s, 2H), 1.21 (t, J=7.2Hz, 3H).

Preparation ethyl 2-methyl-2-(6-nitropyridin-3-yl)propanoate

A solution of ethyl 2-(6-nitropyridin-3-yl)acetate (926 mg, 4.41 mmol)in N,N-dimethylformamide (12 mL) was cooled to 0° C., under a nitrogenatmosphere, and treated with 60% sodium hydride dispersed in mineral oil(186 mg, 4.65 mmol) and stirred at 0° C. for 5 min. Iodomethane (683 mg,4.81 mmol) was then added and the reaction gradually warmed to roomtemperature. Once the purple color had dissipated, the reaction wascooled to 0° C. and treated with 60% sodium hydride dispersed in mineraloil (186 mg, 4.65 mmol) and N,N-dimethylformamide (2 mL), then stirredat 0° C. for 5 min. A second addition of iodomethane (683 mg, 4.81 mmol)was made and the reaction gradually warmed to room temperature over 2 h,then stirred at room temperature for 16 h. After this time, the reactionwas partitioned between water (100 mL) and ethyl acetate (100 mL). Thelayers were separated and the organic phase was washed with water (100mL), then brine (2×100 mL) and dried over sodium sulfate. The dryingagent was removed by filtration and the filtrate concentrated underreduced pressure to afford ethyl2-methyl-2-(6-nitropyridin-3-yl)propanoate as a yellow oil: ¹H NMR (400MHz, DMSO-d₆)□□δ 8.67 (d, J=2.4 Hz, 1H), 8.29 (d, J=8.4 Hz, 1H), 8.20(dd, J=8.4, 2.4 Hz, 1H), 4.12 (q, J=7.2 Hz, 2H), 1.61 (s, 6H), 1.14 (t,J=7.2 Hz, 3H).

Preparation of ethyl 2-(6-aminopyridin-3-yl)-2-methylpropanoate

A mixture of ethyl 2-methyl-2-(6-nitropyridin-3-yl)propanoate (1.03 g,4.32 mmol), ammonium chloride (5.75 g, 107 mmol) and zinc dust (2.81 g,43.0 mmol) in a mixture of 2:1 methanol/water (30 mL) was stirred atroom temperature for 3 h. After this time, the reaction was diluted withethyl acetate (100 mL) and filtered through diatomaceous earth. Thefiltrate was washed with water (100 mL) and the aqueous layer extractedwith ethyl acetate (2×50 mL). The combined organic layers were driedover sodium sulfate, filtered and the filtrate concentrated underreduced pressure to afford ethyl2-(6-aminopyridin-3-yl)-2-methylpropanoate as an orange oil: ¹H NMR (400MHz, DMSO-d₆)□□δ 7.85 (d, J=2.4 Hz, 1H), 7.32 (dd, J=8.4, 2.4 Hz, 1H),6.41 (d, J=8.4 Hz, 1H), 5.83 (bs, 2H), 4.04 (q, J=7.2 Hz, 2H), 1.44 (s,6H), 1.11 (t, J=7.2 Hz, 3H).

Preparation of ethyl2-(6-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)pyridin-3-yl)-2-methylpropanoate

A mixture of ethyl 2-(6-aminopyridin-3-yl)-2-methylpropanoate (775 mg,3.72 mmol), 8-bromo-6-chloroimidazo[1,2-a]pyridine hydrochloride salt(831 mg, 3.10 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (386mg, 0.620 mmol) and cesium carbonate (2.02 g, 6.20 mmol) in toluene (5mL) and 1,4-dioxane (5 mL) was sparged with nitrogen while stirring for10 min. Palladium(II) acetate (76 mg, 0.34 mmol) was then added and thereaction stirred at 100° C. for 2.5 h. After this time, the reaction wascooled to room temperature, diluted with a mixture of 1:4methanol/methylene chloride (150 mL) and filtered through diatomaceousearth. The filtrate was concentrated under reduced pressure and theresulting residue purified by chromatography (silica, gradient, heptaneto 2:3 ethyl acetate/heptane) to afford impure ethyl2-(6-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)pyridin-3-yl)-2-methylpropanoateas a brown solid which was used without further purification in the nextstep: ¹H NMR (400 MHz, DMSO-d₆)□contained an impurity (25%) which madeassignment of the aromatic peaks ambiguous; ESI MS m/z 359.1 [M+H]⁺.

Preparation of2-(6-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)pyridin-3-yl)-2-methylpropan-1-ol

A solution of impure ethyl2-(6-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)pyridin-3-yl)-2-methylpropanoate(575 mg, 1.60 mmol assumed) in anhydrous methylene chloride (15 mL) wascooled to 0° C., under a nitrogen atmosphere, and treated dropwise with1 M diisobutylaluminum hydride in methylene chloride (8.0 mL, 8.0 mmol)over 15 min. When the addition was complete, the reaction was graduallywarm to room temperature over 2 h and stirred at room temperature for 1h. The mixture was carefully treated with water (20 mL) (Caution: addslowly), then potassium sodium tartrate tetrahydrate (400 mg, 1.42 mmol)was added and the reaction stirred at room temperature for a further 30min. After this time, the reaction was diluted with ethyl acetate (100mL) and the layers were separated. The organic phase was dried oversodium sulfate, filtered and the filtrate concentrated under reducedpressure. The resulting residue was purified by chromatography (silica,gradient, heptane to 4:1 ethyl acetate/heptane) to afford2-(6-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)pyridin-3-yl)-2-methylpropan-1-olas an off-white solid: ¹H NMR (400 MHz, DMSO-d₆)□□δ 9.25 (s, 1H), 8.42(d, J=2.0 Hz, 1H), 8.32-8.30 (m, 2H), 7.91 (d, J=1.2 Hz, 1H), 7.68 (dd,J=8.8, 2.8 Hz, 1H), 7.57 (d, J=1.2 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 4.70(t, J=5.2 Hz, 1H), 3.41 (d, J=5.2 Hz, 2H), 1.24 (s, 6H); ESI MS m/z317.8 [M+H]⁺.

Preparation of6-(8-(5-(1-hydroxy-2-methylpropan-2-yl)pyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2-one

A mixture of2-(6-(6-chloroimidazo[1,2-a]pyridin-8-ylamino)pyridin-3-yl)-2-methylpropan-1-ol(195 mg, 0.616 mmol),6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (176 mg,0.679 mmol) and 1 M aqueous sodium carbonate (0.5 mL) in 1,4-dioxane (2mL) was sparged with nitrogen while stirring for 5 min.

Tetrakis(triphenylphosphine)palladium(0) (107 mg, 0.0925 mmol) was thenadded and the reaction heated under microwave irradiation at 145° C. for30 min. After this time, the reaction was cooled to room temperature,diluted with a mixture of 1:4 methanol/methylene chloride (100 mL) andfiltered through diatomaceous earth. The filtrate was concentrated underreduced pressure and the resulting residue purified by chromatography(silica, gradient, methylene chloride to 1:19 methanol/methylenechloride), then trituration with methanol to afford6-(8-(5-(1-hydroxy-2-methylpropan-2-yl)pyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2-oneas a light pink-orange solid: mp 260-266° C. dec; ¹H NMR (400 MHz,DMSO-d₆)□□δ □10.50 (s, 1H), 9.02 (s, 1H), 8.65 (d, J=1.2 Hz, 1H), 8.37(d, J=1.2 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H), 7.96 (d, J=0.8 Hz, 1H), 7.67(dd, J=8.8, 2.8 Hz, 1H), 7.55 (d, J=0.8 Hz, 1H), 7.36-7.32 (m, 2H), 7.23(dd, J=7.6, 1.6 Hz, 1H), 7.07 (d, J=0.8 Hz, 1H), 4.70 (t, J=7.2 Hz, 1H),3.54 (s, 2H), 3.41 (d, J=7.2 Hz, 2H), 1.24 (s, 6H); ESI MS m/z 414.4[M+H]⁺; HPLC, 4.07 min, >99% (AUC).

Example 10

Methyl 6,8-dibromoimidazo[1,2-a]pyridine-5-carboxylate

A 200 mL round bottom flask was charged with methyl6-amino-3,5-dibromopicolinate 1 (8.6 g, 0.0277 mol),2-chloroacetaldehyde (19.93 mL, 0.139 mol, 45% w/w in water) andisopropanol (100 mL). The mixture was stirred at 100° C. for 9 h. Afterthis time, the reaction mixture was concentrated under reduced pressure,and the residue was partitioned between water and ethyl acetate. Theorganic layer was dried over sodium sulfate and the resulting residuewas purified by column chromatography. The solvent was removed by Rotavapor to afford methyl 6,8-dibromoimidazo[1,2-a]pyridine-5-carboxylateas an off-white solid.

Methyl6-bromo-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridine-5-carboxylate

A 200 mL round bottom flask was charged with Methyl6,8-dibromoimidazo[1,2-a]pyridine-5-carboxylate (1.86 g, 0.0055 mol),5-morpholinopyridin-2-amine (1.0 g, 0.0055 mol), Pd₂(dba)₃ (0.25 g,0.00027 mol), Xantphos (0.318, 0.00055 mol), Cs₂CO₃ (3.58 g, 0.011 mol),and dioxane 100 mL. The mixture was stirred at 95° C. for 16 h. Afterthis time, the reaction mixture was filtered through celite and thefiltrate was partitioned between water and ethyl acetate. The organiclayer was dried over sodium sulfate and the resulting residue waspurified by column chromatography. The solvent was removed by Rota vaporto afford methyl6-bromo-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridine-5-carboxylateas a solid.

Methyl6-(1H-indazol-6-yl)-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridine-5-carboxylate

A 2-5 mL micro tube was charged with Methyl6-bromo-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridine-5-carboxylate(0.3 g, 0.00069 mol),6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.2 g,0.00083 mol), Pd₂(dba)₃ (0.04 g, 0.000035 mol), Na₂CO₃/H₂O (1.6 mL,0.0016 mol), and 4.5 mL of dioxane. The mixture was stirred at 150° C.for 1 h in biotage microwave. After this time, the reaction mixture waspartitioned between water and ethyl acetate. The organic layer was driedover sodium sulfate. The resulting residue was purified by columnchromatography. The solvent was removed by Rota vapor to afford methyl6-(1H-indazol-6-yl)-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridine-5-carboxylateas an off-white solid. MS scan (ESI+) m/z: 470.3 (M+H).

Example 11

6-(1H-indazol-6-yl)-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridine-5-carboxylicacid

A 100 mL round bottom flask was charged with Methyl6-(1H-indazol-6-yl)-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridine-5-carboxylate(0.15 g, 0.00032 mol), ethanol (20 mL) and 1 M NaOH (3.2 mL, 0.0032mol). The mixture was stirred at 100° C. for 1 h. After this time, thereaction mixture was concentrated under reduced pressure, and to theresidue was acidified to pH 3 with 1N HCl, extracted withdichloromethane. The organic layer was dried over sodium sulfate. Theresulting residue was purified by column chromatography. The solvent wasremoved by Rota vapor to afford6-(1H-indazol-6-yl)-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridine-5-carboxylicacid as a solid. MS scan (ESI+) m/z: 456.2 (M+H).

Example 12

(6-(1H-indazol-6-yl)-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridin-5-yl)methanol9

A 100 mL round bottom flask was charged with6-(1H-indazol-6-yl)-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridine-5-carboxylicacid (0.15 g, 0.00032 mol) and dichloromethane (30 mL). The solution wascooled to −5° C., DIBAL (1.3 mL, 0.00128 mol, 1 M in dichloromethane)was added dropwise via a syringe. The mixture was stirred at −5° C. for30 min. After this time, the reaction mixture was quenched with methanol(1 mL) and added sat. aqueous Na/K tartrate (15 mL), stirred at RT for30 min, extracted with ethyl acetate. The organic layer was dried oversodium sulfate. The resulting residue was purified by columnchromatography. The solvent was removed by Rota vapor to afford(6-(1H-indazol-6-yl)-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridin-5-yl)methanolas an off-white solid. MS scan (ESI+) m/z: 442.3 (M+H).

Example 13

6-(1H-indazol-6-yl)-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridine-5-carboxamide

A 200 mL round bottom flask was charged with6-(1H-indazol-6-yl)-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridine-5-carboxylicacid (0.18 g, 0.0004 mol), dichloromethane (80 mL), Oxalylchloride (2.4mL, 0.0048 mol, 2M in dichloromethane), and 1 drop of DMF. The mixturewas stirred at 50° C. for 1 h. After this time, the solvent was removedby Rota vapor to afford6-(1H-indazol-6-yl)-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridine-5-carbonylchloride as a solid, which was dissolved in dichloromethane (50 mL),NH₃H₂O (20 mL) was added at 0° C. The mixture was stirred at RT for 30min. After this time, the organic layer was separated and dried oversodium sulfate. The solvent was removed by Rota vapor to afford6-(1H-indazol-6-yl)-8-(5-morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridine-5-carboxamideas a solid. MS scan (ESI+) m/z: 455.2 (M+H).

Example 14

Preparation of 6-ethylpyridin-2-amine

A mixture of 6-chloro-2-aminopyridine (15.0 g, 116 mmol) and[1,3-bis(diphenylphosphino)propane]nickel(II) chloride (5.70 g, 10.5mmol) in anhydrous 1,4-dioxane (450 mL) was treated with 1.1 M solutionof diethylzinc in toluene (225 mL) and the reaction stirred, under anitrogen atmosphere, at reflux for 16 h. After this time, the reactionwas cooled to room temperature, treated with methanol (200 mL) andconcentrated under reduced pressure. The resulting residue was dilutedin brine (500 L) and extracted with a mixture of 9:1 methylenechloride/methanol (3×300 mL). The combined organic layers were driedover sodium sulfate, filtered and the filtrate concentrated underreduced pressure to afford 6-ethylpyridin-2-amine as a brown gel, whichwas used in the next step without further purification: ¹H NMR (400 MHz,CDCl₃) δ 7.36 (t, J=7.6 Hz, 1H), 6.53 (d, J=7.6 Hz, 1H), 6.33 (d, J=7.6Hz, 1H), 4.41 (bs, 2H), 2.64 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H).

Preparation of 3,5-dibromo-6-ethylpyridin-2-amine

To a mixture of 6-ethylpyridin-2-amine (2.00 g, 16.3 mmol) inN,N-dimethylformamide (20 mL) at 10° C. was added N-bromosuccinimide(5.80 g, 32.6 mmol) portion wise over a period of 15 min and thereaction was stirred at room temperature for 2 h. After this time, thereaction was poured into ice-cold water (100 mL) and extracted withethyl acetate (2×50 mL). The combined organic layers were washed withwater (2×25 mL) and dried over anhydrous sodium sulfate. The dryingagent was removed by filtration and the filtrate was concentrated underreduced pressure. The resulting residue was purified by chromatography(silica, gradient, hexane to ethyl acetate) to afford3,5-dibromo-6-ethylpyridin-2-amine as a yellow crystalline solid: ¹H NMR(400 MHz, CDCl₃) δ 7.37 (s, 1H), 4.85 (bs, 2H), 2.76 (q, J=7.6 Hz, 2H),1.22 (t, J=7.6 Hz, 3H).

Preparation of 6,8-dibromo-5-ethylimidazo[1,2-a]pyridine

A mixture of 2-bromo-1,1-diethoxyethane (9.58 mL, 63.7 mmol) and 48%aqueous hydrobromic acid (4.0 mL) was stirred at reflux for 2 h. Afterthis time, the reaction was cooled to room temperature and treated withsodium bicarbonate (3.50 g, 41.6 mmol) until gas evolution ceased. Themixture was filtered and the filtrate diluted with ethanol (180 mL).3,5-Dibromo-6-ethylpyridin-2-amine (17.9 g, 63.9 mmol) was then addedand the mixture stirred at reflux for 16 h. After this time, thereaction was cooled to room temperature and concentrated under reducedpressure to a volume of approximately 10 mL. The resulting suspensionwas filtered and the filter cake washed with cold ethanol (40 mL). Thefilter cake was taken into water (250 mL) and the mixture was adjustedto pH ˜8 with potassium carbonate. The suspension was filtered and thefilter cake dried to a constant weight under vacuum to afford6,8-dibromo-5-ethylimidazo[1,2-a]pyridine as a light brown solid: ¹H NMR(400 MHz, CDCl₃) δ 7.73 (s, 1H), 7.67 (s, 1H), 7.61 (s, 1H), 3.15 (q,J=7.6 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H).

Preparation of6-bromo-5-ethyl-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridin-8-amine

A mixture of 5-(4-ethylpiperazin-1-yl)pyridin-2-amine (3.30 g, 16.0mmol), 6,8-dibromo-5-ethylimidazo[1,2-a]pyridine (5.00 g, 16.4 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (2.14 g, 3.44 mmol) andcesium carbonate (16.4 g, 50.5 mmol) in 1,4-dioxane (200 mL) was spargedwith nitrogen while stirring for 10 min. Palladium(II) acetate (368 mg,1.51 mmol) was then added and the reaction stirred at reflux for 18 h.After this time, the reaction was cooled to room temperature, dilutedwith a mixture of 1:1 methanol/methylene chloride (200 mL) and filteredthrough a pad of diatomaceous earth. The filtrate was concentrated underreduced pressure and the resulting residue purified by chromatography(silica, gradient, 1:24 methanol/methylene chloride to 2:23methanol/methylene chloride) to afford6-bromo-5-ethyl-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridin-8-amineas a brown solid: ¹H NMR (400 MHz, CDCl₃) δ 8.40 (s, 1H), 8.03 (d, J=2.8Hz, 1H), 7.76 (s, 1H), 7.54 (s, 2H), 7.28-7.25 (m, 1H), 6.84 (d, J=9.2Hz, 1H), 3.18-3.13 (m, 4H), 3.10 (q, J=7.6 Hz, 2H), 2.64-2.60 (m, 4H),2.49 (q, J=7.2 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H), 1.13 (t, J=7.2 Hz, 3H).

Preparation of5-ethyl-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-amine

A mixture of6-bromo-5-ethyl-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridin-8-amine(600 mg, 1.40 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (580 mg,2.38 mmol) in 2 M aqueous sodium carbonate (1.8 mL), propylene glycol(0.2 mL) and 1,4-dioxane (12 mL) was sparged with argon while stirringfor 30 min.

Tetrakis(triphenylphosphine)palladium(0) (242 mg, 0.210 mmol) was thenadded and the reaction heated under microwave irradiation at 145° C. for20 min. After this time, the reaction was cooled to room temperature anddiluted with methanol (15 mL). The organic phase was dry loaded ontosilica gel and purified by column chromatography (silica, gradient,methylene chloride to 19:1 methylene chloride/methanol), thentrituration with hexanes to afford5-ethyl-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-amineas a brown solid: mp 216.6° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (s,1H), 8.81 (s, 1H), 8.23 (s, 1H), 8.13 (s, 1H), 7.98 (s, 1H), 7.85-7.80(m, 2H), 7.62 (s, 1H), 7.49 (s, 1H), 7.37 (dd, J=8.8, 2.4 Hz, 1H), 7.28(d, J=9.2 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 3.02-3.01 (m, 4H), 2.82 (q,J=7.2 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H), 1.01 (t, J=6.8 Hz, 3H); CH₂ (m,6H, not observed); MM MS m/z 467.2 [M+H]⁺; HPLC, 11.1 min, 98.4% (AUC).

Example 15

Preparation of 6-bromo-1-methyl-1H-indole

To a stirred suspension of 60% sodium hydride (4.88 g, 122 mmol) intetrahydrofuran (150 mL) was added 6-bromoindole (15.0 g, 76.5 mmol)portionwise, followed by methyl iodide (11.9 g, 83.8 mmol) dropwise andthe mixture stirred at room temperature for 16 h. After this time, thereaction was poured into ice-cold water and extracted with ethyl acetate(2×100 mL). The combined organic layers were washed sequentially withwater, then brine and dried over sodium sulfate. The drying agent wasremoved by filtration and the filtrate concentrated under reducedpressure to afford 6-bromo-1-methyl-1H-indole as a pale red solid: ¹HNMR (400 MHz, CDCl₃) δ □7.49 (m, 2H), 7.22 (dd, J=8.0, 1.6 Hz, 1H), 7.04(d, J=3.2 Hz, 1H), 6.47 (d, J=3.2 Hz, 1H), 3.77 (s, 3H).

Preparation of 2-(6-bromo-1-methyl-1H-indol-3-yl)ethanol

To a solution of 6-bromo-1-methyl-1H-indole (18.0 g, 85.6 mmol) indiethyl ether (180 mL) at 0° C., was added oxalyl chloride (13.1 g, 103mmol) dropwise under a nitrogen atmosphere. The resulting mixture wasallowed to warm to room temperature and stirred for 1 h. After thistime, methanol (15 mL) was added and the reaction stirred at roomtemperature further for 24 h. After this time, the reaction was filteredand the filter cake washed with water (20 mL), then cold diethyl ether(20 mL). The filter cake was dissolved in methylene chloride (100 mL)and dried over sodium sulfate. The drying agent was removed byfiltration and the filtrate concentrated under reduced pressure toafford methyl 2-(6-bromo-1-methyl-1H-indol-3-yl)-2-oxoacetate which wasused in the next step without purification.

A suspension of methyl 2-(6-bromo-1-methyl-1H-indol-3-yl)-2-oxoacetate(18.0 g, 60.8 mmol) in tetrahydrofuran (200 mL) was treated with 2 Mborane dimethylsulfide complex in tetrahydrofuran (121 mL) and stirredat reflux for 5 h. After this time, the reaction was cooled to roomtemperature, diluted with water (50 mL) and saturated aqueous sodiumbicarbonate (100 mL) and extracted with diethyl ether (3×250 mL). Thecombined organic layers were washed sequentially with water and brine,dried over sodium sulfate, filtered and the filtrate concentrated underreduced pressure to afford 2-(6-bromo-1-methyl-1H-indol-3-yl)ethanol asa white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J=8.4 Hz, 1H), 7.46(d, J=1.6 Hz, 2H), 7.22 (dd, J=8.4, 1.6 Hz, 1H), 6.92 (s, 1H), 3.88 (t,J=6.4 Hz, 2H), 3.73 (s, 3H), 2.99 (t, J=6.4 Hz, 3H).

Preparation of2-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)ethanol

A mixture of 2-(6-bromo-1-methyl-1H-indol-3-yl)ethanol (13.0 g, 51.2mmol), bis(pinacolato)diboron (16.8 g, 66.1 mmol) and potassium acetate(14.9 g, 152 mmol) in 1,4-dioxane (160 mL) was sparged with nitrogenwhile stirring for 20 min.Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) methylenechloride adduct (9.17 g, 12.5 mmol) was then added and the reactionstirred at 90° C. for 16 h. After this time, the mixture was cooled toroom temperature, diluted with water (50 mL) and extracted with ethylacetate (2×100 mL). The combined organic layers were washed with brine(2×50 mL) and dried over sodium sulfate. The drying agent was removed byfiltration and the filtrate concentrated under reduced pressure. Theresulting residue was purified by column chromatography (silica,gradient, hexanes to 7:13 ethyl acetate/hexanes) to afford2-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)ethanolas a brown solid: ¹H NMR (400 MHz, DMSO-d₆□□□δ □7.68 (s, 1H), 7.51 (d,J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.20 (s, 1H), 4.64 (t, J=5.2 Hz,1H), 3.75 (s, 3H), 3.64-3.59 (m, 2H), 2.83-2.80 (m, 2H), 1.30 (s, 12H).

Example 16

Preparation of 1-isopropyl-4-(6-nitropyridin-3-yl)piperazine

A mixture of 5-bromo-2-nitropyridine (18.0 g, 88.7 mmol),N-isopropylpiperazine (17.1 g, 133 mmol) and potassium carbonate (36.9g, 267 mol) in dimethylsulfoxide (200 mL) was stirred at 100° C. for 16h. After this time, the reaction was cooled to room temperature, pouredinto ice water (500 mL), stirred for 15 min, then extracted with ethylacetate (2×500 mL). The combined organic layers were dried over sodiumsulfate, filtered and the filtrate concentrated under reduced pressure.The resulting residue was dried under vacuum to a constant weight toafford 1-isopropyl-4-(6-nitropyridin-3-yl)piperazine as a yellow solid:¹H NMR (400 MHz, CDCl₃)□□δ 8.15 (d, J=9.2 Hz, 1H), 8.12 (d, J=2.8 Hz,1H), 7.18 (dd, J=9.2, 2.8 Hz, 1H), 3.46 (t, J=4.8 Hz, 4H), 2.78-2.74 (m,1H), 2.69 (t, J=5.2 Hz, 4H), 1.09 (d, J=10.8 Hz, 6H).

Preparation of 5-(4-isopropylpiperazin-1-yl)pyridin-2-amine

A 500-mL Parr hydrogenation bottle was purged with nitrogen and chargedwith 1-isopropyl-4-(6-nitropyridin-3-yl)piperazine (14.0 g, 55.9 mmol),methanol (140 mL) and 10% palladium on carbon (50% wet, 4.67 g dryweight). The bottle was evacuated, charged with hydrogen gas to apressure of 40 psi and shaken for 5 h at room temperature on a Parrhydrogenation apparatus. After this time, the hydrogen gas was evacuatedand nitrogen charged into the bottle. The catalyst was removed byfiltration through a pad of diatomaceous earth and the filter cakewashed with methanol (50 mL). The filtrate was concentrated underreduced pressure to afford 5-(4-isopropylpiperazin-1-yl) pyridin-2-amineas a brown solid which was used in the next step without purification:¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J=2.8 Hz, 1H), 7.16 (dd, J=8.4, 2.8Hz, 1H), 6.46 (d, J=8.4 Hz, 1H), 3.06 (t, J=4.8 Hz, 4H), 2.75 (m, 1H),2.69 (t, J=4.8 Hz, 4H), 1.09 (d, J=10.4 Hz, 6H), NH₂ (m, 2H, notobserved).

Preparation of 3,5-dibromo-6-chloropyridine-2-amine

To a stirred solution of 6-chloropyridin-2-amine (50.0 g, 388 mmol) inN,N-dimethylformamide (500 mL) at 0° C., was added N-bromosuccinimide(175 g, 972 mmol) portion wise during which an exotherm was observed.The mixture was allowed to warm to room temperature and stirred for 2 h.After this time, the mixture was poured into ice water (2.0 L) and theresulting suspension was filtered. The filter cake was dissolved inmethylene chloride, dried over sodium sulfate, filtered and the filtrateconcentrated under reduced pressure. The resulting residue was driedunder vacuum to a constant weight to afford3,5-dibromo-6-chloropyridine-2-amine as a yellow solid: ¹H NMR (400 MHz,DMSO-d₆) δ 8.09 (s, 1H), 6.88 (bs, 2H); MM MS m/z 286.8 [M+2+H]⁺.

Preparation of 6,8-dibromo-5-chloroimidazo[1,2-a]pyridine

A mixture of 2-bromo-1,1-diethoxyethane (117 mL, 782 mmol) andconcentrated hydrochloric acid (71.0 mL) were stirred at reflux for 2 h.After this time, the reaction was cooled to room temperature and treatedwith sodium bicarbonate (65.7 g, 782 mmol) until gas evolution ceased.The mixture was filtered and the filtrate diluted with ethanol (600 mL).3,5-Dibromo-6-chloropyridin-2-amine (112 g, 391 mmol) was then added andthe mixture stirred at reflux for 16 h. After this time, the reactionwas cooled to room temperature and concentrated under reduced pressure.The resulting residue was diluted with water (500 mL) and treated withpotassium carbonate (108 g, 782 mmol). The precipitated solids werefiltered, dissolved in methylene chloride and dried over sodium sulfate.The drying agent was removed by filtration and the filtrate concentratedunder reduced pressure to afford6,8-dibromo-5-chloroimidazo[1,2-a]pyridine as a brown solid: (400 MHz,DMSO-d₆) δ 8.19 (d, J=0.8 Hz, 1H), 8.02 (s, 1H), 7.78 (d, J=0.8 Hz, 1H);MM MS m/z 310.8 [M+2+H]⁺.

Preparation of6-bromo-5-chloro-N-(5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridin-8-amine

A mixture of 5-(4-isopropylpiperazin-1-yl)pyridin-2-amine (1.42 g, 6.44mmol), 6,8-dibromo-5-chloroimidazo[1,2-a]pyridine (2.00 g, 6.44 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (850 mg, 1.37 mmol) andcesium carbonate (6.50 g, 19.9 mmol) in 1,4-dioxane (100 mL) was purgedwith nitrogen while stirring for 25 min. Palladium(II) acetate (140 mg,0.572 mmol) was added and the reaction purged with argon for a further 5min, then stirred at reflux for 36 h. After this time, the reaction wascooled to room temperature, filtered through a pad of diatomaceous earthand the filter cake washed with a mixture of 1:9 methanol/methylenechloride. The filtrate was concentrated under reduced pressure and theresulting residue purified by column chromatography (silica, gradient,1:49 methanol/methylene chloride to 1:24 methanol/methylene chloride) toafford6-bromo-5-chloro-N-(5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridin-8-amineas a brown solid: ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.06 (d, J=2.8Hz, 1H), 7.78 (s, 1H), 7.75 (d, J=1.2 Hz, 1H), 7.57 (d, J=1.2 Hz, 1H),7.31 (dd, J=9.2, 2.8 Hz, 1H), 6.86 (d, J=9.2 Hz, 1H), 3.20-3.18 (m, 4H),2.79-2.72 (m, 5H), 1.12 (d, J=6.4 Hz, 6H).

Preparation of2-(6-(5-chloro-8-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)-1-methyl-1H-indol-3-yl)ethanol

A mixture of2-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)ethanol(570 mg, 1.89 mmol),6-bromo-5-chloro-N-(5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridin-8-amine(500 mg, 1.11 mmol), propylene glycol (0.1 mL) and 2 M aqueous sodiumcarbonate (1.6 mL) in 1,4-dioxane (15.0 mL) was sparged with nitrogenwhile stirring for 5 min. Tetrakis (triphenylphosphine)palladium(0) (256mg, 0.222 mmol) was then added and the reaction heated under microwaveirradiation at 145° C. for 30 min. After this time, the reaction wascooled to room temperature and diluted with a mixture of 1:1methanol/methylene chloride (20 mL). The organic phase was dry loadedonto silica gel and purified by column chromatography (silica, gradient,methylene chloride to 1:24 methanol/methylene chloride) to afford2-(6-(5-chloro-8-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-a]pyridin-6-yl)-1-methyl-1H-indol-3-yl)ethanolas an off-white solid: mp 181.1° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.09(s, 1H), 8.49 (s, 1H), 8.05 (s, 1H), 7.89-7.88 (m, 1H), 7.71 (s, 1H),7.65 (d, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.43-7.35 (m, 1H), 7.35 (d, J=8.4Hz, 1H), 7.23 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 4.68 (t, J=5.2 Hz, 1H),3.77 (s, 3H), 3.70-3.65 (m, 2H), 3.09-3.08 (m, 4H), 2.87 (t, J=7.2 Hz,2H), 2.72-2.67 (m, 5H), 1.11-1.06 (m, 6H); MM MS m/z 544.2 [M+H]⁺; HPLC12.14 min, 97.0% (AUC).

Example 17

The following compounds were prepared using procedures similar to thosedescribed above Those of ordinary skill in the art of organic synthesiswill recognize when starting materials or reaction conditions should bevaried to obtain the desired compound.

MS data reported in this example was obtained as follows: MS conditions:Electrospray MS is performed on a MICROMASS LCT equipped with aLockSpray source for accurate mass measurements. Spectra are acquired inpositive ion mode from 100-1000 Da at an acquisition rate of 1spectrum/0.9 s with a 0.1 s interscan delay. The instrument is tuned fora resolution of 5000 (FWHM). Every 5^(th) scan is taken from thereference position of the Lockspray source. Leucine enkephalin (556.2771[M+H]⁺) is used as the reference, or lock mass.

Syk−40 μM data was obtained according to the method disclosed in Example18 which follows and represents IC₅₀ values calculated using a 40 μM ATPsolution.

TABLE 1 Syk IC₅₀ and MS Data for Selected Compounds IC₅₀ @ MH+ StructureName 40 uM ATP m/z

N-(3,4- dimethoxyphenyl)-6- (1H-indazol-6- yl)imidazo[1,2-a]pyridin-8-amine 1049.1 386.4

N-[6-(1H-indazol-6- yl)imidazo[1,2- a]pyridin-8-yl]-5,6-dimethoxypyridin-2- amine 3.8 387.3

N-[6-(1H-indazol-6- yl)imidazo[1,2- a]pyridin-8- yl]pyrimidin-4-amine297.2 328.3

N-[6-(1,3-benzothiazol- 5-yl)imidazo[1,2- a]pyridin-8-yl]-5,6-dimethoxypyridin-2- amine 18.2 404.6

7-{8-[(5,6- dimethoxypyridin-2- yl)amino]imidazo[1,2- a]pyridin-6-yl}quinoxalin-2-ol 22.4 415.6

6-{8-[(5,6- dimethoxypyridin-2- yl)amino]imidazo[1,2-a]pyridin-6-yl}-1H- indazol-3-amine 13.3 402.4

N-[6-(3,4-dihydro-2H- 1,4-benzoxazin-6- yl)imidazo[1,2-a]pyridin-8-yl]-5,6- dimethoxypyridin-2- amine 23.7 404.7

N-[6-(1H-indazol-6- yl)imidazo[1,2- a]pyridin-8-yl]-1,5-dimethyl-1H-pyrazol-3- amine 6.2 343.9

6-{8-[(1-ethyl-1H- pyrazol-3- yl)amino]imidazo[1,2- a]pyridin-6-yl}-3,4-dihydro-2H-1,4- benzoxazin-3-one 548.1 375.2

6-{8-[(1-ethyl-1H- pyrazol-3- yl)amino]imidazo[1,2- a]pyridin-6-yl}quinazolin-2-amine 171.3 371.1

1,5-dimethyl-N-[6-(1- methyl-1H-1,3- benzodiazol-6- yl)imidazo[1,2-a]pyridin-8-yl]-1H- pyrazol-3-amine 181.9 358.5

N-[6-(1H-indazol-6- yl)imidazo[1,2- a]pyridin-8-yl]-5-(morpholin-4-yl)pyridin- 2-amine 6.6 412.4

N-[6-(1H-indazol-6- yl)imidazo[1,2- a]pyridin-8-yl]-2-methoxypyrimidin-4- amine 40.5 358.2

N-[6-(3,4-dihydro-2H- 1,4-benzoxazin-6- yl)imidazo[1,2-a]pyridin-8-yl]-1,5- dimethyl-1H-pyrazol-3- amine 153.7 361.8

N-[6-(1H-indazol-6- yl)imidazo[1,2- a]pyridin-8-yl]-1-methyl-1H-pyrazol-3- amine 35.5 330.1

1,5-dimethyl-N-[6-(1- methyl-1H-1,3- benzodiazol-5- yl)imidazo[1,2-a]pyridin-8-yl]-1H- pyrazol-3-amine 187.6 358.4

2-N-[6-(1H-indazol-6- yl)imidazo[1,2- a]pyridin-8-yl]pyridine-2,6-diamine 23.1 342.3

1-(6-{[6-(1H-indazol-6- yl)imidazo[1,2- a]pyridin-8-yl]amino}pyridin-3-yl)- 4-methylpiperidin-4-ol 6 440.5

2-[(6-{[6-(1H-indazol-6- yl)imidazo[1,2- a]pyridin-8-yl]amino}pyridin-3- yl)(methyl)amino] ethan-1-ol 9 400.2

6-(1H-indazol-6-yl)-N- {4H,6H,7H- pyrazolo[3,2- c][1,4]oxazin-2-yl}imidazo[1,2- a]pyridin-8-amine 2 372.3

2-N-[6-(1H-indazol-6- yl)imidazo[1,2- a]pyridin-8-yl]-5-N-(2-methoxyethyl)-5-N- methylpyridin-2,5- diamine 13 414.2

N-[6-(1H-indazol-6- yl)imidazo[1,2- a]pyridin-8-yl]-6- (morpholin-4-yl)pyradazin-3-amine 5 413.4

1-ethyl-N-[6-(1H- indazol-6- yl)imidazo[1,2- a]pyridin-8-yl]-5-methyl-1H-pyrazol-3- amine 39 358.2

6-(8-{[6-(morpholin-4- yl)pyridazin-3- yl]amino}imidazo[1,2-a]pyridin-6-yl)-3,4- dihydro-2H-1,4- benzoxazin-3-one 15 444.8

1-(6-{[6-(1H-indazol-6- yl)imidazo[1,2- a]pyridin-8- yl]amino}pyridin-3-yl)azetidin-3-ol 5 398.1

1-(6-{[6-(1H-indazol-6- yl)imidazo[1,2- a]pyridin-8-yl]amino}pyridin-3-yl)- 3-methylazetidin-3-ol 20 412.4

1-[(6-{[6-(1H-indazol-6- yl)imidazo[1,2- a]pyridin-8-yl]amino}pyridin-3- yl)oxy]-2-methylpropan- 2-ol 8 415.6

[(2S)-4-(6-{[6-(1H- indazol-6- yl)imidazo[1,2- a]pyridin-8-yl]amino}pyridin-3- yl)morpholin-2- yl]methanol 8 442.4

N-[6-(1H-indazol-6-yl)- 5-methylimidazo[1,2- a]pyridin-8-yl]-5-(morpholin-4-yl)pyridin- 2-amine 15 426.2

[(2R)-4-(6-{[6-(1H- indazol-6- yl)imidazo[1,2- a]pyridin-8-yl]amino}pyridin-3- yl)morpholin-2- yl]methanol 5 442.6

N-[6-(1H-indazol-6- yl)imidazo[1,2- a]pyridin-8-yl]-2-(morpholin-4-yl)-1,3- thiazol-4-amine 290.9 418.2

N-{4H,6H,7H- pyrazolo[3,2- c][1,4]oxazin-2-yl}-6- {1H-pyrrolo[3,2-b]pyridin-6- yl}imidazo[1,2- a]pyridin-8-amine 4.5 372

1-methyl-N-(6-{1H- pyrrolo[3,2-b]pyridin-6- yl}imidazo[1,2-a]pyridin-8-yl)-1H- pyrazol-3-amine 23.2 330.1

N-(5-methyl-6-{1H- pyrrolo[3,2-b]pyridin-6- yl}imidazo[1,2-a]pyridin-8-yl)-5- (morpholin-4-yl)pyridin- 2-amine 38 426

1,5-dimethyl-N-(6-{1H- pyrrolo[3,2-b]pyridin-6- yl}imidazo[1,2-a]pyridin-8-yl)-1H- pyrazol-3-amine 10.5 344.1

1-(2-hydroxyethyl)-5-(8- {[5-(morpholin-4- yl)pyridin-2-yl]amino}imidazo[1,2- a]pyridin-6-yl)-2,3- dihydro-1H-1,3-benzodiazol-2-one 25.2 472.1

2-[ethyl({6-[(6-{1H- pyrrolo[3,2-b]pyridin-6- yl}imidazo[1,2-a]pyridin-8- yl)amino]pyridin-3- yl})amino]ethan-1-ol 8.5 414.4

1-(4-{6-[(6-{1H- pyrrolo[3,2-b]pyridin-6- yl}imidazo[1,2- a]pyridin-8-yl)amino]pyridin-3- yl}piperazin-1-yl) ethan-1-one 4.29 453.1

2-[4-({6-[3-(2- hydroxyethyl)-1H-indol- 6-yl]imidazo[1,2- a]pyridin-8-yl}amino)phenyl]-2- methylpropan-1-ol 138 441.4

1-{4-[6-({6-[3-(2- hydroxyethyl)-1H-indol- 6-yl]imidazo[1,2-a]pyridin-8- yl}amino)pyridin-3- yl]piperazin-1-yl}ethan- 1-one 25 496.8

2-{5-methyl-3-[(6-{1H- pyrrolo[3,2-b]pyridin-6- yl}imidazo[1,2-a]pyridin-8-yl)amino]- 1H-pyrazol-1-yl}ethan- 1-one 54 374.2

6-(8-{[5- (hydroxymethyl)-1- methyl-1H-pyrazol-3- yl]amino}imidazo[1,2-a]pyridin-6-yl)-2,3- dihydro-1H-indol-2-one 13 375.1

6-[8-({5-acetyl- 4H,5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}amino)imidazo[1,2- a]pyridin-6-yl]-2,3- dihydro-1H-indol-2-one 18428.2

2-hydroxy-1-(4-{6-[(6- {1H-pyrrolo[3,2- b]pyridin-6- yl}imidazo[1,2-a]pyridin-8- yl)amino]pyridin-3- yl}piperazin-1-yl)ethan- 1-one 2.6469.4

6-(8-{[1-(2- hydroxyethyl)-5-methyl- 1H-pyrazol-3- yl]amino}imidazo[1,2-a]pyridin-6-yl)-2,3- dihydro-1H-indol-2-one 43.2 389.5

{1-methyl-3-[(6-{1H- pyrrolo[3,2-b]pyridin-6- yl}imidazo[1,2-a]pyridin-8-yl)amino]- 1H-pyrazol-5- yl}methanol 20.8 360.1

6-[8-({5- methanesulfonyl- 4H,5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}amino)imidazo[1,2- a]pyridin-6-yl]-2,3- dihydro-1H-indol-2-one 10464.2

N-{5-methanesulfonyl- 4H,5H,6H,7H- pyrazolo[1,5-a]pyrazin- 2-yl]-6-{1H-pyrrolo[3,2-b]pyridin-6- yl}imidazo[1,2- a]pyridin-8-amine 3.7 449

6-(8-{[5-(4- acetylpiperazin-1- yl)pyridin-2- yl]amino}imidazo[1,2-a]pyridin-6-yl)-2,3- dihydro-1H-indol-2-one 15.5 468.3

5-(4-ethylpiperazin-1- yl)-N-(6-{1H- pyrrolo[3,2-b]pyridin-6-yl}imidazo[1,2- a]pyridin-8-yl)pyridin-2- amine 11.3 439.6

2-(6-(8-(5- morpholinopyridin-2- ylamino)imidazo[1,2-a]pyridin-6-yl)-1H- indol-3-yl)ethanol 23.9 455.3

N-(5-(methoxymethyl)- 1-methyl-1H-pyrazol-3- yl)-6-(1H-pyrrolo[3,2-b]pyridin-6- yl)imidazo[1,2- a]pyridin-8-amine 10.9 374.1

N-(5-methyl-6-(1H- pyrrolo[3,2-b]pyridin-6- yl)imidazo[1,2-a]pyridin-8-yl)-6,7- dihydro-4H- pyrazolo[5,1- c][1,4]oxazin-2-amine 7.7386.2

6-(8-(6,7-dihydro-4H- pyrazolo[5,1- c][1,4]oxazin-2- ylamino)-5-methylimidazo[1,2- a]pyridin-6-yl)indolin-2- one 10.8 455.3

1-(2-(6-(1H-pyrrolo[3,2- b]pyridin-6- yl)imidazo[1,2-a]pyridin-8-ylamino)- 6,7- dihydropyrazolo[1,5- a]pyrazin-5(4H)-yl)ethanone 2.8 374.1

6-(8-(5-(2- hydroxypropan-2-yl)-1- methyl-1H-pyrazol-3-ylamino)imidazo[1,2- a]pyridin-6-yl)indolin-2- one 41.5 386.2

2-(6-(8-(6,7-dihydro-4H- pyrazolo[5,1- c][1,4]oxazin-2-ylamino)imidazo[1,2- a]pyridin-6-yl)-1H- indol-3-yl)ethanol 7.1 401.2

5-(8-(5-(2- hydroxypropan-2-yl)-1- methyl-1H-pyrazol-3-ylamino)imidazo[1,2- a]pyridin-6-yl)-1- methyl-1H-benzo[d]imidazol-2(3H)- one 19.7 413.5

2-(3-(6-(1H-pyrrolo[3,2- b]pyridin-6- yl)imidazo[1,2-a]pyridin-8-ylamino)-1- methyl-1H-pyrazol-5- yl)propan-2-ol 44.8 403.1

N-(6-(3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)imidazo[1,2-a]pyridin-8-yl)-6,7- dihydro-4H- pyrazolo[5,1- c][1,4]oxazin-2-amine49.3 415.6

N-(6-(1H-indazol-6-yl)- 5-methylimidazol[1,2- a]pyridin-8-yl)-6,7-dihydro-4H- pyrazolo[5,1- c][1,4]oxazin-2-amine 12.8 418.1

6-(8-(5-cyclopropyl-1H- pyrazol-3- ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2- one 26 388.1

6-(8-(6,7-dihydro-4H- pyrazolo[5,1- c][1,4]oxazin-2-ylamino)imidazo[1,2- a]pyridin-6-yl)indolin-2- one 34 389.7

N-(6-(1H-indol-6- yl)imidazo[1,2- a]pyridin-8-yl)-6,7- dihydro-4H-pyrazolo[5,1- c][1,4]oxazin-2-amine 13 386.1

N-(5-cyclopropyl-1H- pyrazol-3-yl)-6-(1H- indazol-6- yl)imidazo[1,2-a]pyridin-8-amine 22 371

6-(8-(5-(1-hydroxy-2- methylpropan-2- yl)pyridin-2- ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2- one 19 387.4

2-(6-(8-(5-(4- ethylpiperazin-1- yl)pyridin-2- ylamino)imidazo[1,2-a]pyridin-6-yl)-1H- indazol-3-yl)ethanol 92 371.2

2-(6-(8-(5- morpholinopyridin-2- ylamino)imidazo[1,2-a]pyridin-6-yl)-1H- indazol-3-yl)ethanol 17 356.3

N-(5-(4-ethylpiperazin- 1-yl)pyridin-2-yl)-6- (1H-indazol-6-yl)-5-methylimidazo[1,2- a]pyridin-8-amine 17 414.4

N-(5-(4-ethylpiperazin- 1-yl)pyridin-2-yl)-6- (1H-indol-6-yl)-5-methylimidazo[1,2- a]pyridin-8-amine 42 483.6

6-(8-(5-(4- ethylpiperazin-1- yl)pyridin-2-ylamino)-5-methylimidazo[1,2- a]pyridin-6-yl)indolin-2- one 71 456.2

2-(6-(8-(5-(4- ethylpiperazin-1- yl)pyridin-2-ylamino)-5-methylimidazo[1,2- a]pyridin-6-yl)-1H- indol-3-yl)ethanol 301 453.2

6-(8-(5-(4- ethylpiperazin-1- yl)pyridin-2-ylamino)-5-methylimidazo[1,2- a]pyridin-6-yl)-N- methyl-1H-indole-3- carboxamide883 452.3

5-methyl-N-(5- morpholinopyridin-2- yl)-6-(1H-pyrrolo[2,3- b]pyridin-5-yl)imidazo[1,2- a]pyridin-8-amine 166 468.3

1-methyl-6-(5-methyl-8- (5-morpholinopyridin-2- ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2- one 1029 496.2

6-(1H-indazol-6-yl)-5- methyl-N-(5-(piperazin- 1-yl)pyridin-2-yl)imidazo[1,2- a]pyridin-8-amine 128 509.2

5-(8-(5-(4- ethylpiperazin-1- yl)pyridin-2-ylamino)-5-methylimidazo[1,2- a]pyridin-6-yl)-1-(2- methoxyethyl)-1H-benzo[d]imidazol- 2(3H)-one 55 426.1

N-(5-(4-ethylpiperazin- 1-yl)pyridin-2-yl)-5- methyl-6-(2-methyl-1H-indol-6-yl)imidazo[1,2- a]pyridin-8-amine 423 455.1

5-ethyl-N-(5-(4- ethylpiperazin-1- yl)pyridin-2-yl)-6-(1H- indazol-6-yl)imidazo[1,2- a]pyridin-8-amine 252 425.2

5-ethyl-N-(5-(4- ethylpiperazin-1- yl)pyridin-2-yl)-6-(1H-indol-6-yl)imidazo[1,2- a]pyridin-8-amine 272 527.2

6-(5-ethyl-8-(5-(4- ethylpiperazin-1- yl)pyridin-2- ylamino)imidazo[1,2-a]pyridin-6-yl)indolin-2- one 532 466.2

2-(1-methyl-6-(5- methyl-8-(5- morpholinopyridin-2- ylamino)imidazo[1,2-a]pyridin-6-yl)-1H- indol-3-yl)ethanol 320 467.2

5-chloro-N-(5-(4- ethylpiperazin-1- yl)pyridin-2-yl)-6-(1H-indol-6-yl)imidazo[1,2- a]pyridin-8-amine 271 466.2

6-(5-chloro-8-(5-(4- ethylpiperazin-1- yl)pyridin-2-ylamino)imidazo[1,2- a]pyridin-6-yl)indolin-2- one 80 482.2

5-chloro-6-(1H-indazol- 6-yl)-N-(5-(4- isopropylpiperazin-1-yl)pyridin-2- yl)imidazo[1,2- a]pyridin-8-amine 32 483.2

2-(6-(5-chloro-8-(5-(4- ethylpiperazin-1- yl)pyridin-2-ylamino)imidazo[1,2- a]pyridin-6-yl)-1H- indol-3-yl)ethanol 215 472.1

2-(6-(5-chloro-8-(5-(4- ethylpiperazin-1- yl)pyridin-2-ylamino)imidazo[1,2- a]pyridin-6-yl)-1- methyl-1H-indol-3- yl)ethanol278 488.1

5-chloro-N-(5-(4- ethylpiperazin-1- yl)pyridin-2-yl)-6-(1H- indazol-6-yl)imidazo[1,2- a]pyridin-8-amine 14 487.1

6-(5-chloro-8-(5-(4- isopropylpiperazin-1- yl)pyridin-2-ylamino)imidazo[1,2- a]pyridin-6-yl)indolin-2- one 17 516.2

2-(6-(5-chloro-8-(5-(4- isopropylpiperazin-1- yl)pyridin-2-ylamino)imidazo[1,2- a]pyridin-6-yl)-1- methyl-1H-indol-3- yl)ethanol218 530.2

2-(6-(5-chloro-8-(5-(4- isopropylpiperazin-1- yl)pyridin-2-ylamino)imidazo[1,2- a]pyridin-6-yl)-1H- indol-3-yl)ethanol 15 473.1

5-(5-chloro-8-(5-(4- isopropylpiperazin-1- yl)pyridin-2-ylamino)imidazo[1,2- a]pyridin-6-yl)-1-(2- methoxyethyl)-1H-benzo[d]imidazol- 2(3H)-one 12 502.1

N-(6-(1H-indol-6- yl)imidazo[1,2- a]pyridin-8-yl)-5- methyl-4,5,6,7-tetrahydrothiazolo[5,4- c]pyridin-2-amine 72 544.2

N-(6-(1H-indol-6- yl)imidazo[1,2- a]pyridin-8-yl)-5-methylisoxazol-3-amine 49 530.2

5-fluoro-6-(1H-indazol- 6-yl)-N-(5-(4- isopropylpiperazin-1-yl)pyridin-2- yl)imidazo[1,2- a]pyridin-8-amine 68 561.2

N-(6-(1H-pyrazolo[4,3- b]pyridin-6- yl)imidazo[1,2- a]pyridin-8-yl)-5-methyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrazin-2-amine 26.38 401.1

6-(1H-indazol-6-yl)-8- (5-morpholinopyridin-2- ylamino)imidazo[1,2-a]pyridine-5- carboxamide 569.46 330.1

(6-(1H-indazol-6-yl)-8- (5-morpholinopyridin-2- ylamino)imidazo[1,2-a]pyridin-5-yl)methanol 75.48 471.2

6-(1H-indazol-6-yl)-8- (5-morpholinopyridin-2- ylamino)imidazo[1,2-a]pyridine-5-carboxylic acid 4227.2 386.2

methyl 6-(1H-indazol-6- yl)-8-(5- morpholinopyridin-2-ylamino)imidazo[1,2- a]pyridine-5-carboxylate 43.29 455.2

Example 18 Biochemical Syk Assay

A generalized procedure for one standard biochemical Syk Kinase Assaythat can be used to test compounds disclosed in this application is asfollows:

A master mix minus Syk enzyme is prepared containing 1×Cell Signalingkinase buffer (25 mM Tris-HCl, pH 7.5, 5 mM beta-glycerophosphate, 2 mMdithiothreitol, 0.1 mM Na₃VO₄, 10 mM MgCl₂), 0.5 μM Promega PTKBiotinylated peptide substrate 1, 0.01% casein, 0.01% Triton-X100, and0.25% glycerol. A master mix plus Syk enzyme is prepared containing1×Cell Signaling kinase buffer, 0.5 μM PTK Biotinylated peptidesubstrate 1, 0.01% casein, 0.01% Triton-X100, 0.25% glycerol and 0.4ng/well Syk enzyme. Syk enzyme is purchased from Cell SignalingTechnologies, expressed in baculovirus and is an N-terminally GST-taggedfull length human wildtype Syk (accession number NM-00377).

The Syk protein is purified in one step using glutathione-agarose. Thepurity of the final protein preparation is assessed by SDS-PAGE andCoomassie staining. A solution of 200 μM ATP is prepared in water andadjusted to pH 7.4 with 1N NaOH. A quantity of 1.25 μL of compounds in5% DMSO is transferred to a 96-well ½ area Costar polystyrene plate.

Compounds are tested singly and with an 11-point dose-responsive curve(starting concentration is 10-1 μM; 1:2 dilution). A quantity of 18.75μL of master mix minus enzyme (as a negative control) and master mixplus enzyme is transferred to appropriate wells in 96-well ½ area Costarpolystyrene plate. 5 μL of 200 μM ATP is added to that mixture in the96-well ½ area Costar polystyrene plate for final ATP concentration of40 μM.

The reaction is allowed to incubate for 1 hour at room temperature. Thereaction is stopped with Perkin Elmer 1×detection buffer containing 30mM EDTA, 80 nM SA-APC, and 4 nM PT66 Ab. The plate is read usingtime-resolved fluorescence with a Perkin Elmer Envision using excitationfilter 330 nm, emission filter 665 nm, and 2^(nd) emission filter 615 nmIC₅₀ values are subsequently calculated using a linear regressionalgorithm.

Example 19 Ramos Cell pBLNK(Y96) Assay

Another generalized procedure for a standard cellular Syk Kinase Assaythat can be used to test compounds disclosed in this application is asfollows:

Ramos cells are serum starved at 2×10⁶ cells/ml in serum-free RPMI for 1hour in an upright T175 Falcon TC flask. Cells are centrifuged (1100rpm×5 min) and incubated at a density of 0.5×10⁷ cells/ml in thepresence of test compound or DMSO controls for 1 hr at 37° C. Cells arethen stimulated by incubating with 10 μg/ml anti-human IgM F(ab)₂ for 5minutes at 37° C. Cells are pelleted, lysed in 40 μl cell lysis buffer,and mixed with Invitrogen SDS-PAGE loading buffer. 20 μl of cell lysatefor each sample are subject to SDS-PAGE and western blotting withanti-phosphoBLNK(Tyr96) antibody (Cell Signaling Technology #3601) toassess Syk activity and anti-Syk antibody (BD Transduction Labs #611116)to control for total protein load in each lysate. The images aredetected using fluorescent secondary detection systems and the LiCorOdyssey software.

Example 20 B-Cell Proliferation Assay

A generalized procedure for a standard cellular B-cell proliferationassay that can be used to test compounds disclosed in this applicationis as follows:

B-cells are purified from spleens of 8-16 week old Balb/c mice using aB-cell isolation kit (Miltenyi Biotech, Cat #130-090-862). Testcompounds are diluted in 0.25% DMSO and incubated with 2.5×10⁵ purifiedmouse splenic B-cells for 30 min prior to addition of 10 μg/ml of ananti-mouse IgM antibody (Southern Biotechnology Associates Cat #1022-01)in a final volume of 100 μl. Following 24 hr incubation, 1 μCi³H-thymidine is added and plates are incubated an additional 36 hr priorto harvest using the manufacturer's protocol for SPA[³H] thymidineuptake assay system (Amersham Biosciences # RPNQ 0130). SPA-bead basedfluorescence is counted in a microbeta counter (Wallace Triplex 1450,Perkin Elmer).

Example 21 T Cell Proliferation Assay

A generalized procedure for a standard T cell proliferation assay thatcan be used to test compounds disclosed in this application is asfollows:

T cells are purified from spleens of 8-16 week old Balb/c mice using aPan T cell isolation kit (Miltenyi Biotech, Cat #130-090-861). Testcompounds are diluted in 0.25% DMSO and incubated with 2.5×10⁵ purifiedmouse splenic T cells in a final volume of 100 μl in flat clear bottomplates precoated for 90 min at 37° C. with 10 μg/ml each of anti-CD3 (BD#553057) and anti-CD28 (BD #553294) antibodies. Following 24 hrincubation, 1 μCi ³H-thymidine is added and plates incubated anadditional 36 hr prior to harvest using the manufacturer's protocol forSPA[³H] thymidine uptake assay system (Amersham Biosciences # RPNQ0130). SPA-bead based fluorescence was counted in a microbeta counter(Wallace Triplex 1450, Perkin Elmer).

Example 22 CD69 Inhibition Assay

A generalized procedure for a standard assay for the inhibition ofB-cell activity that can be used to test compounds disclosed in thisapplication is as follows:

Total mouse splenocytes are purified from spleens of 8-16 week oldBalb/c mice by red blood cell lysis (BD Pharmingen #555899). Testingcompounds are diluted to 0.5% DMSO and incubated with 1.25×10⁶splenocytes in a final volume of 200 μl in flat clear bottom plates(Falcon 353072) for 60 min at 37° C. Cells are then stimulated with theaddition of 15 μg/ml IgM (Jackson ImmunoResearch 115-006-020), andincubated for 16 hr at 37° C. under an atmosphere containing 5% CO₂.Following the 16 hr incubation, cells are transferred to conical bottomclear 96-well plates and pelleted by centrifugation at 1200×g×5 min.Cells are preblocked by CD16/CD32 (BD Pharmingen #553142), followed bytriple staining with CD19-FITC (BD Pharmingen #553785), CD69-PE (BDPharmingen #553237), and 7AAD (BD Pharmingen #51-68981E). Cells aresorted on a BD FACSCalibur and gated on the CD19⁺/7AAD⁻ population. Thelevels of CD69 surface expression on the gated population is measuredversus test compound concentration.

Example 23 BMMC Degranulation

A generalized procedure for a standard assay for bone-marrow derivedmouse mast cell (BMMC) degranulation that can be used to test compoundsdisclosed in this application is as follows:

Bone-marrow derived mast cells are cultured for >4 weeks with IL-3 (10ng/ml) and SCF (10 ng/ml). The cells are determined to be >90%cKit⁺/FceRI⁺ by FACS analysis at the time of use. Cells (6×10⁷ cells/50ml) are serum-starved in a T150 tissue culture flask for 16 h in theabsence of IL-3 and SCF containing IgEα-DNP at 1 ug/ml. Overnightsensitized cells are washed twice in Tyrodes buffer and resuspended to5×10⁶ cells/ml. 5×10⁵ cells (100 μl) are plated in a 96 well microtiterplate (Falcon 353072) and test compounds are serially diluted to a finalconcentration 0.25% DMSO in the plate for 1 hr at 37° C. under anatmosphere containing 5% CO₂. Wells are treated with a DNP-BSA antigenchallenge (50 ng/ml) and incubated for and additional 30 min at 37° C.Supernatants are assayed for hexosamimidase release versus controlwells. Cell pellets are simultaneously lysed and assessed for totalhexosamimidase release to calculate specific release. Dose-responsecurves are generated using 4-parameter logistical fit and IC₅₀ scalculated.

Example 24 Passive Cutaneous Anaphylaxis (PCA)

The following is a procedure for a standard PCA model used for measuringin vivo IgE anti-DNP Ab sensitization and DNP-BSA antigen for triggeringmast cell degranulation and release of immune regulators that causeacute vessel permeability monitored by Evan's blue dye into the inflamedarea in the mouse ear.

Reagents: Anti-DNP IgE: is supplied as 1.2 mg/ml in a phosphate bufferedsolution with BSA for additional protein and azide for sterility. Thisis diluted 1:100 in sterile PBS as a 12 μg/ml working stock that can befurther diluted in PBS to the appropriate concentration for injection. Afurther 1:5 dilution gives a final 1:500 solution at 2.4 ng/μL. (10μL/ear=24 ng). Sterile PBS alone is used as a negative control.

Evan's blue dye: A 2% stock in saline is sterile filtered and diluted1:1 with DNP-BSA saline solution for a final concentration of 1% forinjection.

DNP-BSA: is made up at 4 mg/mL in sterile ddH₂O. It is further diluted1:1 with sterile saline prior to use. This solution or a furtherdilution in saline is diluted 1:1 with 2% Evan's Blue in sterile salinethat has been filtered through a 0.02 μm filter and refiltered prior toinjection. For these experiments a final solution of 0.5 mg/ml ofDNP-BSA in 1% Evans blue is used, and aliquots of 200 μL are injectedinto the tail vein.

General PCA Protocol Using Intradermal Ear Sensitization

1) On day 0, animals anesthetized with isofluorine are passivelysensitized by intradermal injections of IgE anti-DNP using a 29-gaugeinsulin syringe. By convention, the right ear receives 10 μL intradermalinjection of anti-DNP IgE, while the left ear receives PBS. 2) 20 hrpost sensitization, antigen challenge is administered by tail i.v.injection of DNP-BSA in 200 μL of 1% Evan's blue dye solution in saline.Tails are immersed in warm water prior to iv injection. 3) 30 minutes to2 hr prior to this antigen challenge, drug is delivered sc or po in 10%EtOH/20% cremaphor/70% saline. 4) Animals are sacrifice by CO₂inhalation 30-60 min post antigen challenge and ears are removed forextraction of Evan's blue dye in 500 μL of formamide overnight at 65° C.5) Blood is obtained by cardiac puncture just prior to final cervicaldislocation and processed for plasma to provide PK analysis. 6) Evan'sblue dye is quantified by reading absorbency of 200 μL of extractedsolution in microtiter plates at 620 nm.

Study Design of Experiment

Each animal has one anti-DNP IgE sensitized ear (right ear byconvention) and one PBS control ear (left ear by convention). Groups1-8: represent the vehicle and compound testing arms; Group 9:represents the non-antigen negative control; Group 10: represents thenon-sensitized challenged negative control; Group 11: represents thenon-antigen challenged, non-sensitized negative control group (Groups9-11 represent negative controls for background levels only and requireonly minimal number of animals per group.)

The compounds disclosed in the examples above were tested in the Sykbiochemical assay described herein (Example 18) and certain of thosecompounds exhibited an IC₅₀ value less than or equal to 1 micromolar.Certain of those compounds exhibited an IC₅₀ value less than or equal to100 nM. Certain of those compounds exhibited an IC₅₀ value less than orequal to 10 nM. Certain of those compounds exhibited an IC₅₀ value lessthan or equal to 1 nM.

Some of the compounds disclosed in Example 16 were tested in the B-cellproliferation assay (as described in Example 20) and exhibited an IC₅₀value less than or equal to 10 micromolar. Certain of those compoundsexhibited an IC₅₀ value less than or equal to 1 micromolar.

Certain of those compounds did not inhibit T-cell proliferation and hadIC50 values greater than or equal to 5 micromolar when assayed underconditions described herein (as described in Example 20).

Certain compounds described herein exhibited IC50 values for inhibitionof T-cell proliferation that were at least 3-fold, and in some instances5-fold, greater than the IC50 values of those compounds for inhibitionof B-cell proliferation.

Some of the compounds described herein were tested in an assay forinhibition of B-cell activity (under the conditions described in Example22), and exhibited an IC50 value less than or equal to 10 micromolar.Certain of those compounds exhibited an IC50 value less than or equal to1 micromolar.

Some of the compounds disclosed in described herein exhibited bothbiochemical and cell-based activity. For example, some of the compoundsdescribed herein exhibited an IC50 value less than or equal to 10micromolar in the Syk biochemical assay described herein (Example 18)and an IC50 value less than or equal to 10 micromolar in at least one ofthe cell-based assays (other than the T-cell assay) described herein(Examples 19, 20, 22 or 23). Certain of those compounds exhibited anIC50 value less than or equal to 1 micromolar in the Syk biochemicalassay described herein (Example 19) and an IC50 value less than or equalto 10 micromolar in at least one of the cell-based assays (other thanthe T-cell assay) described herein (Examples 19, 20, 22 or 23). Certainof those compounds exhibited an IC50 value less than or equal to 0.1micromolar and an IC50 value less than or equal to 10 micromolar in atleast one of the cell-based assays (other than the T-cell assay)described herein (Examples 19, 20, 22 or 23).

While some embodiments have been shown and described, variousmodifications and substitutions may be made thereto without departingfrom the spirit and scope of the invention. For example, for claimconstruction purposes, it is not intended that the claims set forthhereinafter be construed in any way narrower than the literal languagethereof, and it is thus not intended that exemplary embodiments from thespecification be read into the claims. Accordingly, it is to beunderstood that the present invention has been described by way ofillustration and not limitations on the scope of the claims.

1-34. (canceled)
 35. A method for treating a patient having a diseaseresponsive to the inhibition of Syk activity, comprising administeringto the patient an effective amount of at least one chemical entitychosen from compounds of Formula I:

and pharmaceutically acceptable salts thereof, wherein R¹ is optionallysubstituted phenyl; R² is chosen from 2,3-dimethyl-2H-indazol-6-yl,1H-indazolyl-6-yl, 1-methyl-1H-indazol-5-yl, 1-methyl-1H-indazol-6-yl,3,4-dihydro-2H-1,4-benzoxazin-3-one-6-yl,1-(2-hydroxyethyl)-1H-benzo[d]imidazol-2(3H)-one-5-yl,3-amino-1H-indazol-6-yl, 1H-pyrrolo[3,2-b]pyridine-6-yl,1,3-benzoxazol-6-yl, 3,4-dihydro-2H-1,4-benzoxazin-6-yl,2-hydroxyquinoxalin-7-yl, 3-aminoquinolin-6-yl,2,3-dihydro-1H-indol-6-yl, 1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one,(3-hydroxyethyl)-1H-indol-6-yl, benzothiazolyl, 2-aminoquinazolin-6-yl,3,3-dimethylindolin-2-one, 2,3-dihydro-1H-indol-2-one,4-fluoro-1H-indazol-6-yl, 5-fluoro-1H-indazol-6-yl, and3-amino-1H-indazol-6-yl; and R³ is chosen from hydrogen, lower alkyl,halogen, carboxamido or CO₂H.
 36. The method according to claim 1,wherein R¹ is phenyl optionally substituted with one or more groupschosen from hydroxy; —NR^(b)R^(c) wherein R^(b) is chosen from hydrogenand C₁-C₆ alkyl optionally substituted with one or two groups chosenfrom hydroxy and —OC₁-C₄ alkyl and R^(c) is independently chosen fromhydrogen and C₁-C₄ alkyl optionally substituted with one or two groupschosen from hydroxy and —OC₁-C₄ alkyl; heterocycloalkyl optionallysubstituted with one or two groups chosen from hydroxy, C₃-C₆cycloalkyl, C₁-C₄ alkyl, —C₁-C₄ alkyl-OH, —C₁-C₄ alkyl-O—C₁-C₄ alkyl,—C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl),—C(O)(C₁-C₄ alkyl), —C(O)(C₁-C₄ alkyl-OH), and —OC₁-C₄ alkyl; —OC₁-C₆alkyl optionally substituted with one or two groups chosen from hydroxy,C₃-C₆ cycloalkyl, C₁-C₄ alkyl, —C₁-C₄ alkyl-OH, —C₁-C₄ alkyl-O—C₁-C₄alkyl, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl),and —OC₁-C₄ alkyl; and C₁-C₆ alkyl optionally substituted with one ortwo groups chosen from hydroxy, C₃-C₆ cycloalkyl, C₁-C₄ alkyl, —C₁-C₄alkyl-OH, —C₁-C₄ alkyl-O—C₁-C₄ alkyl, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), and —OC₁-C₄ alkyl.
 37. A methodfor treating a patient having a disease responsive to the inhibition ofSyk activity, comprising administering to the patient an effectiveamount of at least one chemical entity chosen from compounds of FormulaI:

and pharmaceutically acceptable salts thereof, wherein R¹ is optionallysubstituted phenyl; R² is chosen from 1H-indazolyl-6-yl,1-methyl-1H-indazol-5-yl, 1-methyl-1H-indazol-6-yl,3,4-dihydro-2H-1,4-benzoxazin-3-one-6-yl, 1,3-benzoxazol-6-yl,3-aminoquinolin-6-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, and2,3-dihydro-1H-indol-2-one-6-yl; and R³ is chosen from hydrogen, loweralkyl, halogen, carboxamido or CO₂H.
 38. A method for treating a patienthaving a disease responsive to the inhibition of Syk activity,comprising administering to the patient an effective amount of at leastone chemical entity chosen from compounds of Formula I:

and pharmaceutically acceptable salts thereof, wherein R¹ is optionallysubstituted phenyl; R² is chosen from 2,3-dimethyl-2H-indazol-6-yl,1H-indazolyl-6-yl, 1-methyl-1H-indazol-5-yl, 1-methyl-1H-indazol-6-yl,3,4-dihydro-2H-1,4-benzoxazin-3-one-6-yl,1-(2-hydroxyethyl)-1H-benzo[d]imidazol-2(3H)-one-5-yl,3-amino-1H-indazol-6-yl, 1H-pyrrolo[3,2-b]pyridine-6-yl,1,3-benzoxazol-6-yl, 3,4-dihydro-2H-1,4-benzoxazin-6-yl,2-hydroxyquinoxalin-7-yl, 3-aminoquinolin-6-yl,2,3-dihydro-1H-indol-6-yl, 1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one,(3-hydroxyethyl)-1H-indol-6-yl, benzothiazolyl, 2-aminoquinazolin-6-yl,3,3-dimethylindolin-2-one, 2,3-dihydro-1H-indol-2-one,4-fluoro-1H-indazol-6-yl, 5-fluoro-1H-indazol-6-yl, and3-amino-1H-indazol-6-yl; and R³ is chosen from hydrogen and methyl. 39.A method for treating a patient having a disease responsive to theinhibition of Syk activity, comprising administering to the patient aneffective amount of at least one chemical entity chosen from compoundsof Formula I:

and pharmaceutically acceptable salts thereof, wherein R¹ is optionallysubstituted phenyl; R² is chosen from 2,3-dimethyl-2H-indazol-6-yl,1H-indazolyl-6-yl, 1-methyl-1H-indazol-5-yl, 1-methyl-1H-indazol-6-yl,3,4-dihydro-2H-1,4-benzoxazin-3-one-6-yl,1-(2-hydroxyethyl)-1H-benzo[d]imidazol-2(3H)-one-5-yl,3-amino-1H-indazol-6-yl, 1H-pyrrolo[3,2-b]pyridine-6-yl,1,3-benzoxazol-6-yl, 3,4-dihydro-2H-1,4-benzoxazin-6-yl,2-hydroxyquinoxalin-7-yl, 3-aminoquinolin-6-yl,2,3-dihydro-1H-indol-6-yl, 1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one,(3-hydroxyethyl)-1H-indol-6-yl, benzothiazolyl, 2-aminoquinazolin-6-yl,3,3-dimethylindolin-2-one, 2,3-dihydro-1H-indol-2-one,4-fluoro-1H-indazol-6-yl, 5-fluoro-1H-indazol-6-yl, and3-amino-1H-indazol-6-yl; and R³ is hydrogen.
 40. A method for treating apatient having a disease responsive to the inhibition of Syk activity,comprising administering to the patient an effective amount ofN-(3,4-dimethoxyphenyl)-6-(1H-indazol-6-yl)imidazo[1,2-a]pyridin-8-amine,or a pharmaceutically acceptable salt thereof.
 41. The method accordingto claim 1, wherein the patient is a human.
 42. The method according toclaim 1, wherein the disease responsive to inhibition of Syk activity iscancer.
 43. The method according to claim 1, wherein the diseaseresponsive to inhibition of Syk activity is B-cell lymphoma andleukemia.
 44. The method according to claim 1, wherein the diseaseresponsive to inhibition of Syk activity is rheumatoid arthritis. 45.The method according to claim 1, wherein the disease responsive toinhibition of Syk activity is allergic rhinitis.
 46. The methodaccording to claim 1, wherein the disease responsive to inhibition ofSyk activity is adult respiratory distress syndrome (ARDs).
 47. Themethod according to claim 1, wherein the disease responsive toinhibition of Syk activity is an allergy-induced inflammatory disease.48. The method according to claim 1, wherein the disease responsive toinhibition of Syk activity is multiple sclerosis.
 49. The methodaccording to claim 1, wherein the disease responsive to inhibition ofSyk activity is autoimmune disease.
 50. The method according to claim 1,wherein the disease responsive to inhibition of Syk activity isinflammatory disease.
 51. The method according to claim 1, wherein thedisease responsive to inhibition of Syk activity is acute inflammatoryreaction.
 52. The method according to claim 1, wherein the diseaseresponsive to inhibition of Syk activity is allergic disorder.
 53. Themethod according to claim 1, wherein the disease responsive toinhibition of Syk activity is polycystic kidney disease.